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New Insights into the Role of Nuclear Factor-κB in Cell Growth Regulation

      The nuclear factor (NF)-κB family of eukaryotic transcription factors plays an important role in the regulation of immune response, embryo and cell lineage development, cell apoptosis, cell-cycle progression, inflammation, and oncogenesis. A wide range of stimuli, including cytokines, mitogens, environmental particles, toxic metals, and viral or bacterial products, activate NF-κB, mostly through IκB kinase (IKK)-dependent phosphorylation and subsequent degradation of its inhibitor, the IκB family of proteins. Activated NF-κB translocates into the nucleus where it modulates the expression of a variety of genes, including those encoding cytokines, growth factors, acute phase response proteins, cell adhesion molecules, other transcription factors, and several cell apoptosis regulators. During the past few years, tremendous progress has been achieved in our understanding on how intracellular signaling pathways are transmitted in either a linear or a network manner leading to the activation of NF-κB and subsequent cell growth control. However, a detailed molecular mechanism of NF-κB regulating cell growth has yet to be determined. Elucidation of the relationships between NF-κB activation and cell growth will be important in developing new strategies for the treatment of various human diseases, such as chronic autoimmune disorder and cancer.
      After more than a decade of intensive study, a complex body of knowledge has been accumulated, revealing the molecular mechanisms of signal-induced activation of nuclear factor (NF)-κB, a pivotal transcription factor governing the expression of early response genes involved in cell-to-cell interaction, intercellular communication, cell recruitment or transmigration, amplification or spreading of primary pathogenic signals, and initiation or acceleration of tumorigenesis.
      • Zandi E
      • Karin M
      Bridging the gap: composition, regulation, and physiological function of the IκB kinase complex.
      • Karin M
      • Ben-Neriah Y
      Phosphorylation meets ubiquitination: the control of NF-κB activity.
      • Israel A
      The IKK complex: an integrator of all signals that activate NF-κB?.
      Presently, five mammalian NF-κB family members have been identified and cloned.
      • Chen F
      • Castranova V
      • Shi X
      • Demers LM
      New insights into the role of nuclear factor-κB, a ubiquitous transcription factor in the initiation of diseases.
      • Baldwin Jr, AS
      The NF-κB and IκB proteins: new discoveries and insights.
      • Ghosh S
      • May MJ
      • Kopp EB
      NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses.
      These include NF-κB1 (p50/p105), NF-κB2 (p52/p100), RelA(p65), RelB, and c-Rel. All of these NF-κB family members share a highly conserved Rel homology domain responsible for DNA binding, dimerization, and interaction with IκB, the intracellular inhibitor for NF-κB.
      • Siebenlist U
      • Franzoso G
      • Brown K
      Structure, regulation and function of NF-κB.
      The C-terminal regions of RelA, RelB and c-Rel contain a transactivating domain that is important for NF-κB-mediated gene transactivation. The C-termini of the precursor molecules for p50 and p52, p105 and p100, contain multiple copies of the so-called ankyrin repeat, which is found in IκB family members, including IκB-α, IκB-β, IκB-ε, Bcl3, and Drosophila cactus.
      A wide range of signals, which typically include cytokines, mitogens, environmental and occupational particles, toxic metals, intracellular stresses, viral or bacterial products, and UV light, induce expression of early response genes through the NF-κB family of transcription factors.
      • Karin M
      • Ben-Neriah Y
      Phosphorylation meets ubiquitination: the control of NF-κB activity.
      • Chen F
      • Castranova V
      • Shi X
      • Demers LM
      New insights into the role of nuclear factor-κB, a ubiquitous transcription factor in the initiation of diseases.
      • Pahl HL
      Activators and target genes of Rel/NF-κB transcription factors.
      • Gilmore TD
      The Rel/NF-κB signal transduction pathway: introduction.
      • Sun SC
      • Ballard DW
      Persistent activation of NF-κB by the tax transforming protein of HTLV-1: hijacking cellular IκB kinases.
      In resting cells, NF-κB is sequestered in the cytoplasm in an inactive form through its association with one of several inhibitory molecules, including IκB-α, IκB-β, IκB-ε, p105, and p100. Activation of the NF-κB-signaling cascade results in a complete degradation of IκB or partial degradation of the carboxyl termini of p105 and p100 precursors, allowing the translocation of NF-κB to the nucleus, where it induces transcription (Figure 1). Activated NF-κB binds to specific DNA sequences in target genes, designated as κB-elements, and regulates transcription of genes mediating inflammation, carcinogenesis, and pro- or anti-apoptotic reactions.
      Figure thumbnail gr1
      Figure 1Signaling pathways of NF-κB activation. Extracellular inducers, including cytokines, reactive oxygen species (ROS), and viral and bacterial products, activate IKK through upstream kinases directly or indirectly. Activated IKK phosphorylates N-terminal S32 and S36 residues of IκB-α that is associated with NF-κB p50 and p65 heterodimer. The SCF-β-TrCP complex recognizes phosphorylated IκB-α and modifies IκB-α with polyubiquitin chains. This is followed by proteasome-mediated degradation of IκB-α. After degradation of IκB-α, the activated NF-κB translocates into the nucleus where it binds to the κB-sites of gene promoters or enhancers to up-regulate target gene expression. Line arrows and filled arrows denote the NF-κB signaling pathways;open arrows denote the connections with the by-standing signaling pathways.
      Three IκB proteins, IκB-α, IκB-β, and IκB-ε, have been identified, among which IκB-α is the most abundant inhibitory protein for NF-κB.
      • Chen F
      • Castranova V
      • Shi X
      • Demers LM
      New insights into the role of nuclear factor-κB, a ubiquitous transcription factor in the initiation of diseases.
      All IκB proteins contain two conserved serine (S) residues within their N-terminal domain. Phosphorylation of these conserved S residues in response to inducers, leads to the immediate polyubiquitination of IκB proteins by the SCF-β-TrCP complex, a step that has been shown recently to be inhibited by the nonpathogenic Salmonella bacteria in gut epithelial cells.
      • Neish AS
      • Gewirtz AT
      • Zeng H
      • Young AN
      • Hobert ME
      • Karmali V
      • Rao AS
      • Madara JL
      Prokaryotic regulation of epithelial responses by inhibition of IκBα ubiquitination.
      This modification subsequently targets IκB proteins for rapid degradation by the 26S proteasome.
      • Palombella VJ
      • Rando OJ
      • Goldberg AL
      • Maniatis T
      The ubiquitin-proteasome pathway is required for processing the NF-κB1 precursor protein and the activation of NF-κB.
      A high-molecular weight complex that phosphorylates IκB-α or IκB-β has been characterized recently and named IκB kinase (IKK) complex. This complex contains two catalytic subunits, IKK-α and IKK-β, and a structural component named NEMO/IKKγ/IKKAP.
      • Woronicz JD
      • Gao X
      • Cao Z
      • Rothe M
      • Goeddel DV
      IκB kinase-β: NF-κB activation and complex formation with IκB kinase-α and NIK.
      • Mercurio F
      • Zhu H
      • Murray BW
      • Shevchenko A
      • Bennett BL
      • Li J
      • Young DB
      • Barbosa M
      • Mann M
      • Manning A
      • Rao A
      IKK-1 and IKK-2: cytokine-activated IκB kinases essential for NF-κB activation.
      An earlier report by Cohen and colleagues
      • Cohen L
      • Henzel WJ
      • Baeuerle PA
      IKAP is a scaffold protein of the IκB kinase complex.
      suggested the presence of a scaffold protein named IKK complex-associated protein (IKAP) in the IKK complex, which could not be confirmed in other studies. A later study by the group, who originally identified IKAP, indicated that the observed association of IKAP with IKK was because of a nonstrict elusion condition of chromatographic extracts during the purification of IKK.
      • Krappmann D
      • Hatada EN
      • Tegethoff S
      • Li J
      • Klippel A
      • Giese K
      • Baeuerle PA
      • Scheidereit C
      The IκB kinase (IKK) complex is tripartite and contains IKKγ but not IKAP as a regular component.
      Recently, two groups independently reported the identification of a novel protein, CIKS/Act1, associated with the IKK complex and suggested that CIKS/Act1 functions as an anchoring proteins in the assembly of the IKK complex and in providing a possible connection between IKK and c-Jun-N-terminal kinase signaling.
      • Li X
      • Commane M
      • Nie H
      • Hua X
      • Chatterjee-Kishore M
      • Wald D
      • Haag M
      • Stark GR
      Act1, an NF-κB-activating protein.
      • Leonardi A
      • Chariot A
      • Claudio E
      • Cunningham K
      • Siebenlist U
      CIKS, a connection to IκB kinase and stress-activated protein kinase.
      IKK-α and IKK-β share 50% sequence homology. Both proteins contain an amino terminal kinase domain, a carboxyl terminal region with a leucine zipper, and a helix-loop-helix domain. In vitro or in vivo studies indicate that although both IKK-α and IKK-β are capable of phosphorylating IκB-α on ser32 and ser36, IKK-β is more potent in IκB-α phosphorylation induced by proinflammatory stimuli. However, a distinct IKK complex, named IKKi/ε that does not contain IKK-α, -β, or -γ, was recently identified in T cells.
      • Israel A
      The IKK complex: an integrator of all signals that activate NF-κB?.
      • Tojima Y
      • Fujimoto A
      • Delhase M
      • Chen Y
      • Hatakeyama S
      • Nakayama K
      • Kaneko Y
      • Nimura Y
      • Motoyama N
      • Ikeda K
      • Karin M
      • Nakanishi M
      NAK is an IκB kinase-activating kinase.
      IKKi/ε shares 27% homology with IKK-α and IKK-β and possibly mediates NF-κB-activating kinase signaling and PMA/PKCε-induced S36 phosphorylation of IκB-α and NF-κB activation.
      • Israel A
      The IKK complex: an integrator of all signals that activate NF-κB?.
      • Tojima Y
      • Fujimoto A
      • Delhase M
      • Chen Y
      • Hatakeyama S
      • Nakayama K
      • Kaneko Y
      • Nimura Y
      • Motoyama N
      • Ikeda K
      • Karin M
      • Nakanishi M
      NAK is an IκB kinase-activating kinase.
      Although the signaling pathways leading to the activation of NF-κB have been well defined, a number of questions remain to be answered. For example, it is unclear exactly how many protein subunits comprise a naïve and activated IKK complex, respectively; how the various signaling pathways converge on this kinase complex; what upstream kinases contribute to the phosphorylation and activation of IKK. It is also unclear whether other substrates, in addition to IκB or NF-κB family members, can be phosphorylated by IKK. Regarding the functional aspects of NF-κB transcription factor, we know that although NF-κB is important and involved in the regulation of cell apoptosis, cell-cycle transition, and carcinogenic transformation,
      • Huang S
      • DeGuzman A
      • Bucana CD
      • Fidler IJ
      Nuclear factor-κB activity correlates with growth, angiogenesis, and metastasis of human melanoma cells in nude mice.
      the detailed interconnections among NF-κB activation, cell cycle, and apoptosis are still undefined. Considering the fact that aberrant activation of NF-κB is associated with a wide range of human diseases, elucidation of molecular mechanisms determining NF-κB activation and expression of its various functions may lead to the development of novel preventive and therapeutic strategies for many diseases including chronic inflammation and cancer.

      Roles of NF-κB Activation in Cell Apoptosis

      Programmed cell death, or apoptosis, is an essential mechanism for any multicellular organism to eliminate cells that are in excess or potentially dangerous.
      • Strasser A
      • O'Connor L
      • Dixit VM
      Apoptosis signaling.
      Most apoptotic cells are characterized by unique morphological features, such as membrane blebbing, cell shrinking, cytosolic and nuclear condensation, and breakdown of chromosomal DNA. Depending on the use of different initiating caspases, signal-induced apoptosis can be roughly divided into receptor-mediated extrinsic apoptosis and mitochondrial-mediated intrinsic apoptosis (Figure 2).
      • Ashkenazi A
      • Dixit VM
      Death receptors: signaling and modulation.
      • Green DR
      • Reed JC
      Mitochondria and apoptosis.
      The extrinsic apoptotic pathway is triggered as a consequence of ligand binding to death receptors, including tumor necrosis factor (TNF)-R, Fas, OX40, CD40, and 4–1BB, which contain conserved protein-protein-binding domains termed death domains. These receptors recruit procaspases, mainly caspase-8, via adapter molecules. The intrinsic apoptotic pathway is mediated by mitochondria through release of apoptosis-promoting factors, including cytochrome c, apoptosis-inducing factor, and Diablo/Smac.
      • De Laurenzi V
      • Melino G
      Apoptosis. The little devil of death.
      • Du C
      • Fang M
      • Li Y
      • Li L
      • Wang X
      Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition.
      • Verhagen AM
      • Ekert PG
      • Pakusch M
      • Silke J
      • Connolly LM
      • Reid GE
      • Moritz RL
      • Simpson RJ
      • Vaux DL
      Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins.
      • Susin SA
      • Lorenzo HK
      • Zamzami N
      • Marzo I
      • Snow BE
      • Brothers GM
      • Mangion J
      • Jacotot E
      • Costantini P
      • Loeffler M
      • Larochette N
      • Goodlett DR
      • Aebersold R
      • Siderovski DP
      • Penninger JM
      • Kroemer G
      Molecular characterization of mitochondrial apoptosis-inducing factor.
      Cytochrome c forms a complex with a cytosolic protein named Apaf-1, a flavoprotein with homology to plant ascorbate reductases and bacterial NADH oxidases, to activate caspase-9.
      • Susin SA
      • Lorenzo HK
      • Zamzami N
      • Marzo I
      • Snow BE
      • Brothers GM
      • Mangion J
      • Jacotot E
      • Costantini P
      • Loeffler M
      • Larochette N
      • Goodlett DR
      • Aebersold R
      • Siderovski DP
      • Penninger JM
      • Kroemer G
      Molecular characterization of mitochondrial apoptosis-inducing factor.
      Whereas apoptosis-inducing factor released from the intermembranous space of damaged mitochondria induces apoptosis in a caspase-independent manner, Smac/Diablo released from mitochondria promotes apoptosis by binding to and antagonizing XIAP, cIAP1, and cIAP2, allowing the activation of caspases.
      • Du C
      • Fang M
      • Li Y
      • Li L
      • Wang X
      Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition.
      • Verhagen AM
      • Ekert PG
      • Pakusch M
      • Silke J
      • Connolly LM
      • Reid GE
      • Moritz RL
      • Simpson RJ
      • Vaux DL
      Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins.
      Both activated caspase-8 from the extrinsic apoptotic pathway and activated caspase-9 from the intrinsic apoptotic pathway cleave and activate effector caspases, mainly caspase-3 to execute an apoptotic process. These apoptotic pathways, however, were compromised in many cases because of the activation of caspase-independent signaling cascades that function to block the apoptotic responses. A good example is TNF-R-mediated activation of NF-κB that induces expression of anti-apoptotic proteins, including caspase inhibitors, such as cIAP1, cIAP2, and XIAP, and mitochondria membrane stabilizers, such as Bcl-xl and Bfl-1.
      • LaCasse EC
      • Baird S
      • Korneluk RG
      • MacKenzie AE
      The inhibitors of apoptosis (IAPs) and their emerging role in cancer.
      • Reed JC
      Bcl-2 family proteins.
      • Dahl AM
      • Klein C
      • Andres PG
      • London CA
      • Lodge MP
      • Mulligan RC
      • Abbas AK
      Expression of bcl-X(L) restores cell survival, but not proliferation off effector differentiation, in CD28-deficient T lymphocytes.
      Figure thumbnail gr2
      Figure 2Possible targeting point of anti-apoptotic signals from NF-κB. Intrinsic (open arrows) and extrinsic (filled arrows) apoptosis pathways are depicted. The effector caspases, such as caspase-3 and caspase-7, are activated by upstream initiator caspases, caspase-8 and caspase-9. The initiator caspases themselves are activated by either ligands binding to the death receptor complex or cytochrome c released from damaged mitochondria. An anti-apoptotic effect of NF-κB is achieved through its up-regulation of IAPs that inhibits caspases and Bcl-xl that protects mitochondria from further damaging.→, activation; ⊣, inhibition.
      Tumor suppressor protein, p53, has been considered to be one of the major contributors of cell apoptosis in response to a variety of stress inducers. As a transcription factor, p53 is able to up-regulate the expression of genes involved in either reactive oxygen species production or reactive oxygen species metabolism, including quinone oxidoreductase (Pig 3), proline oxidase (Pig 6) homologues, glutathione transferase (Pig 12), and glutathione peroxidase (GPx).
      • Polyak K
      • Xia Y
      • Zweier JL
      • Kinzler KW
      • Vogelstein B
      A model for p53-induced apoptosis.
      Moreover, p53 also activates the expression of several genes that directly control or regulate the process of apoptosis. These genes include Bax, Fas, Fas ligand (FasL), IGF-BP3, PAG608,
      • Amundson SA
      • Myers TG
      • Fornace Jr, AJ
      Roles for p53 in growth arrest and apoptosis: putting on the brakes after genotoxic stress.
      ei24 (Pig 8),
      • Gu Z
      • Flemington C
      • Chittenden T
      • Zambetti GP
      ei24, a p53 response gene involved in growth suppression and apoptosis.
      and Noxa.
      • Oda E
      • Ohki R
      • Murasawa H
      • Nemoto J
      • Shibue T
      • Yamashita T
      • Tokino T
      • Taniguchi T
      • Tanaka N
      Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis.
      With the identification of role of NF-κB in transcriptional regulation of several pro-apoptotic genes, such as fas and fasl, controversy raged as reports demonstrating that NF-κB protected cells from apoptosis in some types of cells were matched by a similar number of reports demonstrating that it did not in other types of cells.
      • Barkett M
      • Gilmore TD
      Control of apoptosis by Rel/NF-κB transcription factors.
      • Aggarwal BB
      Apoptosis and nuclear factor-κB: a tale of association and dissociation.
      Based primarily on earlier studies, NF-κB was initially considered a pro-apoptotic factor because of its rapid activation in cells in response to apoptotic signals and its involvement in the expression of some apoptotic genes, including TNF-α, c-myc, and fasl.
      • Hsu SC
      • Gavrilin MA
      • Lee HH
      • Wu CC
      • Han SH
      • Lai MZ
      NF-κB-dependent Fas ligand expression.
      • Matsui K
      • Fine A
      • Zhu B
      • Marshak-Rothstein A
      • Ju ST
      Identification of two NF-κB sites in mouse CD95 ligand (Fas ligand) promoter: functional analysis in T cell hybridoma.
      More recent work, however, has altered this view and revealed an anti-apoptotic effect of NF-κB in response to a variety of apoptotic stimuli.
      The direct evidence for the anti-apoptotic effects of NF-κB is provided by gene knockout studies in which the genes encoding either members of NF-κB family proteins or upstream kinases were disrupted. RelA (p65)-deficient mice die during embryonic development through apoptosis of hepatocytes.
      • Beg AA
      • Sha WC
      • Bronson RT
      • Ghosh S
      • Baltimore D
      Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB.
      IKK-β gene knockout mice and IKK-β/IKK-α double-knockout mice die as embryos and show massive liver cell apoptosis,
      • Li ZW
      • Chu W
      • Hu Y
      • Delhase M
      • Deerinck T
      • Ellisman M
      • Johnson R
      • Karin M
      The IKKβ subunit of IκB kinase (IKK) is essential for nuclear factor κB activation and prevention of apoptosis.
      • Tanaka M
      • Fuentes ME
      • Yamaguchi K
      • Durnin MH
      • Dalrymple SA
      • Hardy KL
      • Goeddel DV
      Embryonic lethality, liver degeneration, and impaired NF-κB activation in IKK-β-deficient mice.
      • Li Q
      • Estepa G
      • Memet S
      • Israel A
      • Verma IM
      Complete lack of NF-κB activity in IKK1 and IKK2 double-deficient mice: additional defect in neurulation.
      a phenotype similar to the response of NF-κB p65 gene knockout mice. In addition, knockout of the IKK-α gene results in perinatal lethality of mice with an increased thickness of the skin because of the deficiency of keratinocyte differentiation.
      • Gerondakis S
      • Grossmann M
      • Nakamura Y
      • Pohl T
      • Grumont R
      Genetic approaches in mice to understand Rel/NF-κB and IκB function: transgenics and knockouts.
      Male mice with an inactivated X-linked gene encoding IKK-γ/NEMO, an essential modulator of the IKK complex for NF-κB activation, die at mid-gestation because of a massive apoptosis of cortical and medulla lymphocytes in the thymus, in addition to degeneration of the liver.
      • Makris C
      • Godfrey VL
      • Krahn-Senftleben G
      • Takahashi T
      • Roberts JL
      • Schwarz T
      • Feng L
      • Johnson RS
      • Karin M
      Female mice heterozygous for IKKγ/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti.
      • Schmidt-Supprian M
      • Bloch W
      • Courtois G
      • Addicks K
      • Israel A
      • Rajewsky K
      • Pasparakis M
      NEMO/IKKγ-deficient mice model incontinentia pigmenti.
      Female mice deficient in the IKK-γ/NEMO gene manifest a unique dermatopathy because of the apoptosis of keratinocytes and consequent abnormal pigmentation, a characteristic strikingly similar to that of the human X-linked dominant, male-lethal genetic disease—incontinential pigmenti or Bloch-Sulzberger Syndrome. Cross-breeding of relA or IKK-β gene knockout mice with TNF-R1 or TNF-α gene knockout mice revealed partial rescue of embryonic lethality, suggesting that NF-κB deficiency sensitized cells in response to TNF-α-mediated cytotoxicity.
      • Rosenfeld ME
      • Prichard L
      • Shiojiri N
      • Fausto N
      Prevention of hepatic apoptosis and embryonic lethality in RelA/TNFR-1 double knockout mice.
      • Doi TS
      • Marino MW
      • Takahashi T
      • Yoshida T
      • Sakakura T
      • Old LJ
      • Obata Y
      Absence of tumor necrosis factor rescues RelA-deficient mice from embryonic lethality.
      Similarly, mice deficient in both TNF-R1 and IKK-β showed an attenuated embryonic liver apoptosis.
      • Li Q
      • Van Antwerp D
      • Mercurio F
      • Lee KF
      • Verma IM
      Severe liver degeneration in mice lacking the IkB kinase 2 gene.
      Other compelling evidence linking NF-κB with an anti-apoptotic effect is based on the studies indicating that NF-κB is a priming factor for liver regeneration after partial hepatectomy.
      • Fausto N
      • Laird AD
      • Webber EM
      Liver regeneration. 2. Role of growth factors and cytokines in hepatic regeneration.
      This priming effect of NF-κB might be through its transcriptional regulation for survival genes or anti-apoptotic genes whose products can block stress signal-induced cell death, a process critically involved in cell proliferation and transformation. Candidate anti-apoptotic genes targeted by NF-κB include those encoding the cell-cycle regulatory protein cyclin D1,
      • Joyce D
      • Bouzahzah B
      • Fu M
      • Albanese C
      • D'Amico M
      • Steer J
      • Klein JU
      • Lee RJ
      • Segall JE
      • Westwick JK
      • Der CJ
      • Pestell RG
      Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-κB-dependent pathway.
      • Hinz M
      • Krappmann D
      • Eichten A
      • Heder A
      • Scheidereit C
      • Strauss M
      NF-κB function in growth control: regulation of cyclin D1 expression and G0/G1-to-S-phase transition.
      • Guttridge DC
      • Albanese C
      • Reuther JY
      • Pestell RG
      • Baldwin Jr, AS
      NF-κB controls cell growth and differentiation through transcriptional regulation of cyclin D1.
      the mitochondrial membrane-stabilizing proteins Blf-1 and Bcl-xl,
      • Chen F
      • Demers LM
      • Vallyathan V
      • Lu Y
      • Castranova V
      • Shi X
      Involvement of 5′-flanking κB-like sites within bcl-x gene in silica-induced Bcl-x expression.
      • Chen C
      • Edelstein LC
      • Gelinas C
      The Rel/NF-κB family directly activates expression of the apoptosis inhibitor Bcl-x(L).
      the caspase inhibitors cIAP1/cIAP2 and XIAP, and the TNF receptor-associated factors TRAF1 and TRAF2.
      • Wang CY
      • Mayo MW
      • Korneluk RG
      • Goeddel DV
      • Baldwin Jr, AS
      NF-κB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation.
      It should be noted that several reports suggest that NF-κB is also a pro-apoptotic factor in FasL-induced cell death.
      • Ivanov VN
      • Lee RK
      • Podack ER
      • Malek TR
      Regulation of Fas-dependent activation-induced T cell apoptosis by cAMP signaling: a potential role for transcription factor NF-κB.
      • Kasibhatla S
      • Brunner T
      • Genestier L
      • Echeverri F
      • Mahboubi A
      • Green DR
      DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-κB and AP-1.
      This argument is primarily based on earlier observations that NF-κB can regulate the artificial promoter activity of the fasl gene, a gene encoding an important activator of apoptosis through a CD95/Fas- and Fas-associated death domain (FADD)-mediated caspase-8 activation pathway.
      • Ashkenazi A
      • Dixit VM
      Death receptors: signaling and modulation.
      However, both promoter truncation studies of the fasl gene and somatic cell mutagenesis studies of IKK-γ indicate that NF-κB is not required for the fasl gene expression.
      • Rivera-Walsh I
      • Cvijic ME
      • Xiao G
      • Sun SC
      The NF-κB signaling pathway is not required for Fas ligand gene induction but mediates protection from activation-induced cell death.
      • Latinis KM
      • Norian LA
      • Eliason SL
      • Koretzky GA
      Two NFAT transcription factor binding sites participate in the regulation of CD95 (Fas) ligand expression in activated human T cells.
      Nevertheless, pro-apoptotic or anti-apoptotic effects of NF-κB might depend on the cellular context in combination with a bewildering variety of activators.
      Further support for the anti-apoptotic effect of NF-κB comes from observations in which NF-κB can protect cortical neurons from β-amyloid peptide-induced apoptosis in Alzheimer's disease.
      • Bales KR
      • Du Y
      • Dodel RC
      • Yan GM
      • Hamilton-Byrd E
      • Paul SM
      The NF-κB/Rel family of proteins mediates Ab-induced neurotoxicity and glial activation.
      • Guo Q
      • Robinson N
      • Mattson MP
      Secreted b-amyloid precursor protein counteracts the proapoptotic action of mutant presenilin-1 by activation of NF-κB and stabilization of calcium homeostasis.
      Exposure of cortical neurons to β-amyloid peptide increased levels of IκB-α mRNA and protein and a consequent decrease in NF-κB activity.
      • Bales KR
      • Du Y
      • Dodel RC
      • Yan GM
      • Hamilton-Byrd E
      • Paul SM
      The NF-κB/Rel family of proteins mediates Ab-induced neurotoxicity and glial activation.
      Elevation of NF-κB activity by pretreatment of these cells with an antisense oligonucleotide to IκB-α protected them from β-amyloid peptide-induced apoptosis. Conversely, blockade of NF-κB activity by κB decoy DNA was associated with enhanced β-amyloid peptide-induced mitochondrial dysfunction and cell apoptosis.
      • Guo Q
      • Robinson N
      • Mattson MP
      Secreted b-amyloid precursor protein counteracts the proapoptotic action of mutant presenilin-1 by activation of NF-κB and stabilization of calcium homeostasis.
      Moreover, data from the studies of rodent models of stroke or cardiac arrest suggested that NF-κB might possibly prevent ischemic neuronal degeneration.
      • Yu Z
      • Zhou D
      • Bruce-Keller AJ
      • Kindy MS
      • Mattson MP
      Lack of the p50 subunit of nuclear factor-κB increases the vulnerability of hippocampal neurons to excitotoxic injury.
      The protective role of NF-κB on neurons was attributed to NF-κB-mediated transcription of genes encoding Bcl-2, Mn-SOD, and proteins regulating cellular calcium homeostasis.
      • Mattson MP
      • Camandola S
      NF-κB in neuronal plasticity and neurodegenerative disorders.
      The vast majority of studies focused on the regulatory roles of NF-κB on apoptosis suggest that NF-κB is acting on the upstream pathways of apoptosis, either negatively or positively. Conversely, a few recent studies have demonstrated the possible regulation of apoptotic molecules on NF-κB. Of potential interest regarding regulation of NF-κB by apoptotic molecules are the observations of cross-competition between NF-κB and p53, a major pro-apoptotic protein.
      • Yang JP
      • Hori M
      • Takahashi N
      • Kawabe T
      • Kato H
      • Okamoto T
      NF-κB subunit p65 binds to 53BP2 and inhibits cell death induced by 53BP2.
      • Wadgaonkar R
      • Phelps KM
      • Haque Z
      • Williams AJ
      • Silverman ES
      • Collins T
      CREB-binding protein is a nuclear integrator of nuclear factor-κB and p53 signaling.
      • Shao J
      • Fujiwara T
      • Kadowaki Y
      • Fukazawa T
      • Waku T
      • Itoshima T
      • Yamatsuji T
      • Nishizaki M
      • Roth JA
      • Tanaka N
      Overexpression of the wild-type p53 gene inhibits NF-κB activity and synergizes with aspirin to induce apoptosis in human colon cancer cells.
      • Ariumi Y
      • Kaida A
      • Lin JY
      • Hirota M
      • Masui O
      • Yamaoka S
      • Taya Y
      • Shimotohno K
      HTLV-1 tax oncoprotein represses the p53-mediated trans-activation function through coactivator CBP sequestration.
      • Pise-Masison CA
      • Mahieux R
      • Jiang H
      • Ashcroft M
      • Radonovich M
      • Duvall J
      • Guillerm C
      • Brady JN
      Inactivation of p53 by human T-cell lymphotropic virus type 1 Tax requires activation of the NF-κB pathway and is dependent on p53 phosphorylation.
      • Ikeda A
      • Sun X
      • Li Y
      • Zhang Y
      • Eckner R
      • Doi TS
      • Takahashi T
      • Obata Y
      • Yoshioka K
      • Yamamoto K
      p300/CBP-dependent and -independent transcriptional interference between NF-κB RelA and p53.
      The molecular events identified thus far as mediators of cross-competition between NF-κB and p53 can be roughly classified into two categories: the upstream kinases or other regulatory molecules that relay input signals into NF-κB and p53, and co-factors that affect transcriptional activities of NF-κB and p53. An earlier study conducted by Jung and colleagues
      • Jung M
      • Kondratyev A
      • Lee SA
      • Dimtchev A
      • Dritschilo A
      ATM gene product phosphorylates IκB-α.
      indicated that ATM, a major kinase responsible for DNA damage-induced N-terminal phosphorylation of p53, was involved in IκB-α phosphorylation in SV40 large T-transformed fibroblasts in response to ionizing radiation. In nontransformed fibroblasts, however, Ashburner and colleagues
      • Ashburner BP
      • Shackelford RE
      • Baldwin Jr, AS
      • Paules RS
      Lack of involvement of ataxia telangiectasia mutated (ATM) in regulation of nuclear factor-kB (NF-kB) in human diploid fibroblasts.
      demonstrated a lack of involvement of ATM in IκB-α phosphorylation. In an in vitro study, Liu and colleagues
      • Liu L
      • Kwak YT
      • Bex F
      • Garcia-Martinez LF
      • Li XH
      • Meek K
      • Lane WS
      • Gaynor RB
      DNA-dependent protein kinase phosphorylation of IκBα and IκBβ regulates NF-κB DNA binding properties.
      reported that DNA-dependent protein kinase (DNA-PK), a kinase phosphorylating p53 in response to DNA damage, was able to phosphorylate the carboxyl terminus of IκB-α protein. On the functional level, the first evidence of mutual functional regulation between NF-κB and p53 was from the observation that p53 could antagonize NF-κB activity by cross-competition for a limiting pool of the co-activator, p300.
      • Wadgaonkar R
      • Phelps KM
      • Haque Z
      • Williams AJ
      • Silverman ES
      • Collins T
      CREB-binding protein is a nuclear integrator of nuclear factor-κB and p53 signaling.
      In contrast, two recent studies indicated that p53 might activate NF-κB through an unknown mechanism
      • Ryan KM
      • Ernst MK
      • Rice NR
      • Vousden KH
      Role of NF-κB in p53-mediated programmed cell death.
      or stimulate the activity of NF-κB through induction of its target gene, p21Waf1, which inhibits cyclin E/Cdk2 activity and blocks its ability to compete with NF-κB for co-factors, such as p300 and CBP.
      • Perkins ND
      • Felzien LK
      • Betts JC
      • Leung K
      • Beach DH
      • Nabel GJ
      Regulation of NF-κB by cyclin-dependent kinases associated with the p300 coactivator.
      Further evidence indicating that apoptotic molecules regulate NF-κB comes from study of caspase cleavage of NF-κB p65 subunit or IκB-α protein.
      • Levkau B
      • Scatena M
      • Giachelli CM
      • Ross R
      • Raines EW
      Apoptosis overrides survival signals through a caspase-mediated dominant-negative NF-κB loop.
      • Barkett M
      • Xue D
      • Horvitz HR
      • Gilmore TD
      Phosphorylation of IκBα inhibits its cleavage by caspase CPP32 in vitro.
      • Reuther JY
      • Baldwin Jr, AS
      Apoptosis promotes a caspase-induced amino-terminal truncation of IκBα that functions as a stable inhibitor of NF-κB.
      The cleavage of p65 by caspase-3 leads to a loss of the carboxyl-terminal transactivation domain.
      • Levkau B
      • Scatena M
      • Giachelli CM
      • Ross R
      • Raines EW
      Apoptosis overrides survival signals through a caspase-mediated dominant-negative NF-κB loop.
      The carboxyl terminal truncated p65 is transcriptionally inactive. The cleavage of IκB-α by caspase-3 has been observed in γ-radiation-induced apoptosis and NF-κB inhibition-induced apoptosis.
      • Reuther JY
      • Baldwin Jr, AS
      Apoptosis promotes a caspase-induced amino-terminal truncation of IκBα that functions as a stable inhibitor of NF-κB.
      • Jung M
      • Zhang Y
      • Dimtchev A
      • Dritschilo A
      Impaired regulation of nuclear factor-κB results in apoptosis induced by γ radiation.
      A caspase-3 cleavage site has been identified in the region of amino acids 26 to 32 of human IκB-α and 32 to 37 of chicken IκB-α protein.
      • Barkett M
      • Xue D
      • Horvitz HR
      • Gilmore TD
      Phosphorylation of IκBα inhibits its cleavage by caspase CPP32 in vitro.
      The cleavage site of caspase-3 on IκB-α with the amino acid sequence D-R-H-D-S resembles the consensus caspase-3 cleavage site, D-X-X-D-G/S/A, where X represents any amino acid residue. Cleavage of IκB-α by caspase-3 creates a N-terminal truncated IκB-α protein that is resistant to degradation by proteasome in response to inducers of NF-κB, but is able to bind to and suppress NF-κB. Therefore, the role of caspase-3 cleavage on IκB-α and p65 is to ensure that the anti-apoptotic gene is suppressed and apoptotic process is not interrupted once the cells are committed to apoptotic elimination.
      In contrast, several studies indicate that caspases might also participate in the activation of NF-κB under certain circumstances. One example supporting this notion is the involvement of Dredd, a caspase encoded by Drosophila dredd gene, in the endoprotease cleavage of the Relish protein.
      • Silverman N
      • Zhou R
      • Stoven S
      • Pandey N
      • Hultmark D
      • Maniatis T
      A drosophila IκB kinase complex required for relish cleavage and antibacterial immunity.
      Structurally similar to human p100 and p105, two precursor proteins of NF-κB family, Relish contains a N-terminal Rel homology domain and a C-terminal IκB-like region. On lipopolysaccharide stimulation, Relish undergoes a rapid cleavage between the Rel homology domain and IκB-like region. Proteasome inhibitors failed to prevent the cleavage of Relish. In contrast, introducing a dominant-negative mutant of Dredd to inhibit the caspase activity of Dredd significantly blocked the cleavage of Relish, indicating caspase, rather than proteasome, is required for the activation of NF-κB-like protein in Drosophila. In addition, in mammalian cells, caspase-8, caspase-10, and MRIT, three death effector domain-containing proteins, have been shown to be able to activate upstream signals, such as NIK and IKK, leading to the activation of NF-κB.
      • Chaudhary PM
      • Eby MT
      • Jasmin A
      • Kumar A
      • Liu L
      • Hood L
      Activation of the NF-κB pathway by caspase 8 and its homologs.
      This activity seems to be mainly dependent on the interaction between the prodomain of caspases and IKK. Furthermore, several recent studies suggested that other apoptosis-inducing proteins, such as Nod2, an Apaf-1 family member, and Bcl I0 and vCLAP, two caspase-recruitment domain-containing proteins, could also activate NF-κB through the interaction with IKK-γ subunit of IKK complex.
      • Ogura Y
      • Inohara N
      • Benito A
      • Chen FF
      • Yamaoka S
      • Nunez G
      Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-κB.
      • Ruland J
      • Duncan GS
      • Elia A
      • del Barco Barrantes I
      • Nguyen L
      • Plyte S
      • Millar DG
      • Bouchard D
      • Wakeham A
      • Ohashi PS
      • Mak TW
      Bcl10 is a positive regulator of antigen receptor-induced activation of NF-κB and neural tube closure.
      • Poyet JL
      • Srinivasula SM
      • Alnemri ES
      vCLAP, a caspase recruitment domain-containing protein of equine herpesvirus-2, persistently activates the IκB kinases through oligomerization of IKKγ.
      However, it is hard to reconcile these observations with the notions that NF-κB is repressed in the cells undergoing apoptosis.
      • Gu Z
      • Flemington C
      • Chittenden T
      • Zambetti GP
      ei24, a p53 response gene involved in growth suppression and apoptosis.
      • Reuther JY
      • Baldwin Jr, AS
      Apoptosis promotes a caspase-induced amino-terminal truncation of IκBα that functions as a stable inhibitor of NF-κB.
      • Jung M
      • Zhang Y
      • Dimtchev A
      • Dritschilo A
      Impaired regulation of nuclear factor-κB results in apoptosis induced by γ radiation.

      NF-κB and Cell-Cycle Regulation

      It has been known for decades that multiple signals are required to maintain proper cell growth and tissue homeostasis.
      • Nurse P
      A long twentieth century of the cell cycle and beyond.
      Most cells within a normal tissue may be forced out of the active cell cycling into a quiescent (G0) state from which they may re-enter cell cycling under some future circumstances. In a mature tissue, cells may be induced to terminal differentiation by relinquishing their proliferative or cell-cycling potential. Control of the orderly progression of dividing cells through the G1, S, G2, and M phases of the cell cycle in eukaryotic cells relies on a series of cell-cycle regulatory proteins, mainly cyclins that exert their function by binding to and activating a number of specific cyclin-dependent kinases (CDKs). The CDK activity is further modulated by kinases and phosphatases that phosphorylate and dephosphorylate CDK, respectively. Moreover, CDKs are subject to regulation by association with one of a number of specific CDK inhibitors or cell-cycle checkpoint proteins, such as p21Waf1, p16INK4a, p27Kip1,
      • Shackelford RE
      • Kaufmann WK
      • Paules RS
      Cell cycle control, checkpoint mechanisms, and genotoxic stress.
      and growth arrest and DNA-damage protein 45 (GADD45) (Figure 3).
      • Sheikh MS
      • Hollander MC
      • Fornance Jr, AJ
      Role of Gadd45 in apoptosis.
      Figure thumbnail gr3
      Figure 3Involvement of NF-κB in cell-cycle regulation. NF-κB may facilitate cell-cycle transition from G1 to S phase by antagonizing the activation or function of p53 and up-regulating cyclin D1 gene expression. NF-κB may also promote G2- to M-phase transition by down-regulating the expression of GADD45, a G2/M phase blocker that inhibits CDC2/cyclin B complex.→, activation; ⊣, inhibition.
      Overwhelming evidence during recent years demonstrates that a variety of stress inducers, including DNA-damaging agents, activate checkpoint function of cells, leading to a cell-cycle arrest. Several checkpoints exist in the G1/S phase, G2phase, and M phase of cell cycle. In mammalian cells, the control of the S-phase checkpoint requires the p53 tumor suppressor protein that governs the expression of CDK inhibitor, p21Waf1.
      • Sandor V
      • Senderowicz A
      • Mertins S
      • Sackett D
      • Sausville E
      • Blagosklonny MV
      • Bates SE
      P21-dependent g(1)arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228.
      • Jimenez GS
      • Khan SH
      • Stommel JM
      • Wahl GM
      p53 regulation by post-translational modification and nuclear retention in response to diverse stresses.
      The activation of the G2/M phase checkpoint is dependent on the phosphorylation-dependent inactivation of CDC25C phosphatase by checkpoint kinases 1 or 2 (Chk1 or Chk2) and the induction of GADD45, an inhibitor for the G2/M phase cyclin B/CDC2 complex.
      • Graves PR
      • Yu L
      • Schwarz JK
      • Gales J
      • Sausville EA
      • O'Connor PM
      • Piwnica-Worms H
      The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01.
      • Hutchins JR
      • Hughes M
      • Clarke PR
      Substrate specificity determinants of the checkpoint protein kinase Chk1.
      An additional checkpoint, the spindle checkpoint, has been identified in a later stage of M phase.
      • Nurse P
      A long twentieth century of the cell cycle and beyond.
      • Shackelford RE
      • Kaufmann WK
      • Paules RS
      Cell cycle control, checkpoint mechanisms, and genotoxic stress.
      This checkpoint arrests mitotic progression if the spindle is not properly assembled, or if the chromosomes are not correctly oriented and attached to the spindle. All of the checkpoints are essential for maintaining genomic stability by allowing cells to have enough time to repair damage, thus, protecting the organism from the deleterious consequences of mutation.
      The relationship between NF-κB and apoptosis has been intensively explored during the last few years, whereas only limited information is available regarding the possible involvement of NF-κB in cell-cycle regulation in cellular response to a variety of stress signals. A critical role for NF-κB in cell-cycle progression was suggested by earlier observations that NF-κB activity was elevated during the G0 to G1 cell-cycle transition in mouse fibroblasts.
      • Baldwin Jr, AS
      • Azizkhan JC
      • Jensen DE
      • Beg AA
      • Coodly LR
      Induction of NF-κB DNA-binding activity during the G0-to-G1 transition in mouse fibroblasts.
      A series of recent studies has begun to elucidate that in addition to fibroblasts, NF-κB activation was required for cell cycling in other types of cells, such as regenerating liver cells and estrogen receptor-negative breast cancer cells.
      • Baldwin Jr, AS
      • Azizkhan JC
      • Jensen DE
      • Beg AA
      • Coodly LR
      Induction of NF-κB DNA-binding activity during the G0-to-G1 transition in mouse fibroblasts.
      • Cressman DE
      • Greenbaum LE
      • Haber BA
      • Taub R
      Rapid activation of post-hepatectomy factor/nuclear factor κB in hepatocytes, a primary response in the regenerating liver.
      • Duckett CS
      • Perkins ND
      • Leung K
      • Agranoff AB
      • Nabel GJ
      Cytokine induction of nuclear factor κB in cycling and growth-arrested cells. Evidence for cell cycle-independent activation.
      • Yamada Y
      • Kirillova I
      • Peschon JJ
      • Fausto N
      Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor.
      • Biswas DK
      • Cruz AP
      • Gansberger E
      • Pardee AB
      Epidermal growth factor-induced nuclear factor κB activation: a major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells.
      It was also found that the levels of NF-κB activation were linked to signaling that controls cell-cycle progression in HeLa cells and Jurkat T cells.
      • Perkins ND
      • Felzien LK
      • Betts JC
      • Leung K
      • Beach DH
      • Nabel GJ
      Regulation of NF-κB by cyclin-dependent kinases associated with the p300 coactivator.
      • Bash J
      • Zong WX
      • Gelinas C
      c-Rel arrests the proliferation of HeLa cells and affects critical regulators of the G1/S-phase transition.
      Inhibition of NF-κB caused impairment of cell-cycle progression in human glioma cells
      • Otsuka G
      • Nagaya T
      • Saito K
      • Mizuno M
      • Yoshida J
      • Seo H
      Inhibition of nuclear factor-κB activation confers sensitivity to tumor necrosis factor-a by impairment of cell cycle progression in human glioma cells.
      and a retarded G1/S transition in HeLa cells.
      • Kaltschmidt B
      • Kaltschmidt C
      • Hehner SP
      • Droge W
      • Schmitz ML
      Repression of NF-κB impairs HeLa cell proliferation by functional interference with cell cycle checkpoint regulators.
      The identification of NF-κB binding sites in the promoter region of cyclin D1 gene provided direct evidence for the contributions of NF-κB to the cell cycle.
      • Joyce D
      • Bouzahzah B
      • Fu M
      • Albanese C
      • D'Amico M
      • Steer J
      • Klein JU
      • Lee RJ
      • Segall JE
      • Westwick JK
      • Der CJ
      • Pestell RG
      Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-κB-dependent pathway.
      • Hinz M
      • Krappmann D
      • Eichten A
      • Heder A
      • Scheidereit C
      • Strauss M
      NF-κB function in growth control: regulation of cyclin D1 expression and G0/G1-to-S-phase transition.
      • Guttridge DC
      • Albanese C
      • Reuther JY
      • Pestell RG
      • Baldwin Jr, AS
      NF-κB controls cell growth and differentiation through transcriptional regulation of cyclin D1.
      • Biswas DK
      • Cruz AP
      • Gansberger E
      • Pardee AB
      Epidermal growth factor-induced nuclear factor κB activation: a major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells.
      Cyclin D1, in association with cyclin-dependent kinases, CDK4 and CDK6, promotes G1/S phase transition through CDK-dependent phosphorylation of pRb, thereby releasing the transcription factor E2F, which is required for the activation of S phase-specific genes.
      • Nevins JR
      E2F: a link between the Rb tumor suppressor protein and viral oncoproteins.
      • Sherr CJ
      • Roberts JM
      Inhibitors of mammalian G1 cyclin-dependent kinases.
      • Weinberg RA
      The retinoblastoma protein and cell cycle control.
      Two NF-κB binding sites in the human cyclin D1 promoter have been identified. Inhibition of NF-κB by a degradation-resistant IκB-α caused a pronounced reduction of serum-induced cyclin D1 expression accompanied by a decrease of cyclin D1-associated kinase activity and delayed phosphorylation of pRb.
      In contrast, several recent reports also indicated that NF-κB activation is necessary to cause cell-cycle arrest and/or induce cells to commit to terminal differentiation. Overexpression of NF-κB p65 or c-Rel arrests G1/S cell-cycle transition in pro-B cells and HeLa cells, respectively.
      • Bash J
      • Zong WX
      • Gelinas C
      c-Rel arrests the proliferation of HeLa cells and affects critical regulators of the G1/S-phase transition.
      • Sheehy AM
      • Schlissel MS
      Overexpression of RelA causes G1 arrest and apoptosis in a pro-B cell line.
      In HeLa cells, overexpression of c-Rel arrests cells at the G1/S phase because of the stabilization of p53 protein, which can subsequently activate the expression of p21Waf1, a potent inhibitor of CDK2.
      • Bash J
      • Zong WX
      • Gelinas C
      c-Rel arrests the proliferation of HeLa cells and affects critical regulators of the G1/S-phase transition.
      The elevated levels of p21Waf1 correlated with the accumulation of the hypophosphorylated form of pRb and a decrease in E2F DNA binding. It is unclear how overexpression of c-Rel resulted in a prolonged half-life of p53 protein. In pro-B cells, although overexpression of c-Rel exhibited no effect on cell-cycle regulation, overexpression of p65 caused G1 arrest and subsequent apoptosis. This G1-arresting effect of p65, however, seems to be dependent on cell developmental stage, because overexpression of p65 did not cause G1 arrest in mature B cells. It remains unsettled whether manipulation of NF-κB signaling using protein overexpression can lead to consequences that are physiologically relevant. If it is, one may speculate that inhibition of NF-κB should cause over-cycling or hyperproliferation. Indeed, data obtained by gene inactivation of IKK-α in the mouse indicated an unexpected excessive proliferation of the skin basal layer because of the absence of epidermal differentiation.
      • Takeda K
      • Takeuchi O
      • Tsujimura T
      • Itami S
      • Adachi O
      • Kawai T
      • Sanjo H
      • Yoshikawa K
      • Terada N
      • Akira S
      Limb and skin abnormalities in mice lacking IKKα.
      • Hu Y
      • Baud V
      • Delhase M
      • Zhang P
      • Deerinck T
      • Ellisman M
      • Johnson R
      • Karin M
      Abnormal morphogenesis but intact IKK activation in mice lacking the IKKα subunit of IκB kinase.
      NF-κB activity could not be found in keratinocytes from IKK-α-null mouse skin. These results point to a unique role for NF-κB in the epidermis, that is, NF-κB forces keratinocytes out of cell cycle and subsequent terminal differentiation. In this regard, the response of the epidermal keratinocytes to NF-κB seem to be opposite from that of other cell types, such as lymphocytes and macrophages, where NF-κB seems to promote cell-cycle transition.
      • Joyce D
      • Bouzahzah B
      • Fu M
      • Albanese C
      • D'Amico M
      • Steer J
      • Klein JU
      • Lee RJ
      • Segall JE
      • Westwick JK
      • Der CJ
      • Pestell RG
      Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-κB-dependent pathway.
      • Hinz M
      • Krappmann D
      • Eichten A
      • Heder A
      • Scheidereit C
      • Strauss M
      NF-κB function in growth control: regulation of cyclin D1 expression and G0/G1-to-S-phase transition.
      • Guttridge DC
      • Albanese C
      • Reuther JY
      • Pestell RG
      • Baldwin Jr, AS
      NF-κB controls cell growth and differentiation through transcriptional regulation of cyclin D1.
      • Biswas DK
      • Cruz AP
      • Gansberger E
      • Pardee AB
      Epidermal growth factor-induced nuclear factor κB activation: a major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells.
      Although most of the studies so far addressed the effects of NF-κB on G1/S phase regulation, the question of whether NF-κB also contributes to G2/M phase transition has not been explored. In a recent study in human bronchial epithelial cell line, BEAS-2B, we found that NF-κB inhibition by stable expression of a kinase mutated form of IKK-β potentiated toxic metal-induced G2/M cell-cycle arrest.
      • Chen F
      • Lu Y
      • Zhang Z
      • Vallyathan V
      • Ding M
      • Castranova V
      • Shi X
      Opposite effect of NF-κB and c-Jun-N-terminal kinase on p53-independent GADD45 induction by arsenite.
      First, flow cytometric analysis demonstrated that at 48 hours after arsenite treatment, BEAS-2B cells expressing a kinase-mutated form of IKK-β showed a marked dose-dependent increase of cells arrested in the G2/M phase and a corresponding decrease in the number of cells in G1 phase. Second, a dose-dependent induction of GADD45 protein was observed in cells treated with arsenite. This induction of GADD45 by arsenite seems to be dependent on the activation of c-Jun-N-terminal kinase, because blockage of c-Jun-N-terminal kinase activation by expression of a dominant-negative SEK1 vector decreased the induction of GADD45. On the other hand, inhibition of NF-κB by expressing a kinase-mutated form of IKK-β increased GADD45 induction by arsenite. Third, analysis for the expression of CDC25 family members revealed that arsenite induced de novo CDC25A expression, but markedly reduced the levels of CDC25B and CDC25C proteins, two phosphatases dephosphorylating and activating CDC2/cyclin B complex required for the transition of the cell cycle from G2 to M phase. The effects of Cr(VI) on the regulation of the cell cycle were also determined and revealed to be more complicated. Although Cr(VI) was able to induce GADD45 and suppress both CDC25B and CDC25C, it had no effect on CDC25A. Cell-cycle-profiling studies showed that whereas a lower concentration of Cr(VI) (0.25 μg/ml) promoted cell-cycle transition, higher concentrations of Cr(VI) (1 to 4 μg/ml) arrested cells at S phase. In the case of vanadate-induced cell-cycle regulation, the cell-cycle-arresting effect of vanadate seems to be dependent on the status of NF-κB activation. In normal epithelial cells, vanadate exhibited less effect on cell-cycle transition. However, in the cells where NF-κB activation was specifically inhibited, vanadate showed a marked G2/M phase-arresting effect. However, vanadate was unable to induce the expression of GADD45, an inhibitor of cyclin B/CDC2 complex required for G2/M transition (Chen et al, unpublished observations).

      NF-κB and Oncogenesis

      The ability of NF-κB to suppress apoptosis and to regulate cell-cycle transition clearly indicates that NF-κB may participate in many aspects of oncogenesis. Indeed, elevation of NF-κB activity is evident in a number of human cancers, including breast cancer,
      • Sovak MA
      • Bellas RE
      • Kim DW
      • Zanieski GJ
      • Rogers AE
      • Traish AM
      • Sonenshein GE
      Aberrant nuclear factor-κB/Rel expression and the pathogenesis of breast cancer.
      non-small cell lung carcinoma,
      • Mukhopadhyay T
      • Roth JA
      • Maxwell SA
      Altered expression of the p50 subunit of the NF-κB transcription factor complex in non-small cell lung carcinoma.
      thyroid cancer,
      • Gilmore TD
      • Koedood M
      • Piffat KA
      • White DW
      Rel/NF-κB/IκB proteins and cancer.
      T- or B- lymphocyte leukemia,
      • Bargou RC
      • Leng C
      • Krappmann D
      • Emmerich F
      • Mapara MY
      • Bommert K
      • Royer HD
      • Scheidereit C
      • Dorken B
      High-level nuclear NF-κB and Oct-2 is a common feature of cultured Hodgkin/Reed-Sternberg cells.
      melanoma,
      • Devalaraja MN
      • Wang DZ
      • Ballard DW
      • Richmond A
      Elevated constitutive IκB kinase activity and IκBα phosphorylation in Hs294T melanoma cells lead to increased basal MGSA/GRO-α transcription.
      colon cancer,
      • Dejardin E
      • Deregowski V
      • Chapelier M
      • Jacobs N
      • Gielen J
      • Merville MP
      • Bours V
      Regulation of NF-κB activity by IκB-related proteins in adenocarcinoma cells.
      bladder cancer,
      • Sumitomo M
      • Tachibana M
      • Ozu C
      • Asakura H
      • Murai M
      • Hayakawa M
      • Nakamura H
      • Takayanagi A
      • Shimizu N
      Induction of apoptosis of cytokine-producing bladder cancer cells by adenovirus-mediated IκBα overexpression.
      and several virally induced tumors.
      • Miwa M
      • Kushida S
      • Maeda N
      • Fang J
      • Kawamura T
      • Kameyama T
      • Uchida K
      Pathogenesis and prevention of HTLV-1-associated diseases.
      • Berger C
      • Brousset P
      • McQuain C
      • Knecht H
      Deletion variants within the NF-κB activation domain of the LMP1 oncogene in acquired immunodeficiency syndrome-related large cell lymphomas, in prelymphomas and atypical lymphoproliferations.
      • Nasti G
      • Vaccher E
      • Errante D
      • Tirelli U
      Malignant tumors and AIDS.
      The earliest evidence for a role for NF-κB in oncogenic transformation has been derived from the fact that v-Rel, a highly oncogenic retroviral homologue of c-Rel, causes carcinogenesis in avian lymphoid cells.
      • Gilmore TD
      • Koedood M
      • Piffat KA
      • White DW
      Rel/NF-κB/IκB proteins and cancer.
      Later studies suggested that v-Rel also has the capacity of transforming mammalian cells in vivo.
      • Carrasco D
      • Rizzo CA
      • Dorfman K
      • Bravo R
      The v-rel oncogene promotes malignant T-cell leukemia/lymphoma in transgenic mice.
      Transgenic mice expressing v-Rel under the control of the T-cell-specific lck promoter develop T-cell lymphomas. Inhibition of NF-κB by overexpression of a degradation-resistant IκB-α delays the development of T-cell lymphomas and prolongs the survival of v-Rel transgenic mice.
      • Carrasco D
      • Rizzo CA
      • Dorfman K
      • Bravo R
      The v-rel oncogene promotes malignant T-cell leukemia/lymphoma in transgenic mice.
      Chromosomal alterations of NF-κB family genes provided additional evidence for the role of NF-κB in oncogenesis. It has been demonstrated that genes encoding c-Rel, NF-κB2 (p100/p52), p65/RelA, and Bcl-3 proteins are all located within breakpoint regions of the genome that are involved in oncogenic rearrangements or amplifications. Rearrangement of nfkb2 gene by t(10,14) chromosomal translocation causes deletions of sequences encoding the ankyrin repeat motif of p100. Consequently, this carboxyl terminal truncated p100 is constitutively located in the nucleus of cells, which has been originally found in a case of B-cell non-Hodgkin's lymphoma and observed in a number of lymphoid neoplasms, particularly cutaneous lymphomas.
      • Neri A
      • Chang CC
      • Lombardi L
      • Salina M
      • Corradini P
      • Maiolo AT
      • Chaganti RS
      • Dalla-Favera R
      B cell lymphoma-associated chromosomal translocation involves candidate oncogene lyt-10, homologous to NF-κB p50.
      • Fracchiolla NS
      • Lombardi L
      • Salina M
      • Migliazza A
      • Baldini L
      • Berti E
      • Cro L
      • Polli E
      • Maiolo AT
      • Neri A
      Structural alterations of the NF-κB transcription factor lyt-10 in lymphoid malignancies.
      • Liptay S
      • Seriu T
      • Bartram CR
      • Schmid RM
      Germline configuration of nfkb2, c-rel and bcl3 in childhood acute lymphoblastic leukemia (ALL).
      Rearrangement and amplification of c-Rel gene has also been found in numerous non-Hodgkin's lymphomas and cancer cell lines.
      • Gilmore TD
      • Koedood M
      • Piffat KA
      • White DW
      Rel/NF-κB/IκB proteins and cancer.
      • Houldsworth J
      • Mathew S
      • Rao PH
      • Dyomina K
      • Louie DC
      • Parsa N
      • Offit K
      • Chaganti RS
      REL proto-oncogene is frequently amplified in extranodal diffuse large cell lymphoma.
      The bcl-3 gene, which encodes an IκB-like protein that regulates transcriptional activity of NF-κB p50 or p52 homodimer, was identified as a [t(14, 19)(q32;q13.1)] chromosomal translocation in many cases of chronic lymphocytic leukemia.
      • Michaux L
      • Dierlamm J
      • Wlodarska I
      • Bours V
      • Van den Berghe H
      • Hagemeijer A
      t(14;19)/BCL3 rearrangements in lymphoproliferative disorders: a review of 23 cases.
      Unlike rearrangement of the nfkb2 gene, alterations at the bcl-3 locus do not truncate or change the coding sequence, but rather cause overexpression of bcl-3 mRNA. In malignant Hodgkin and Reed-Sternberg (H/RS) cells from Hodgkin's lymphoma, mutations in the IκB-α gene have been detected and are suggested to cause a sustained activation of NF-κB.
      • Cabannes E
      • Khan G
      • Aillet F
      • Jarrett RF
      • Hay RT
      Mutations in the IκBα gene in Hodgkin's disease suggest a tumour suppressor role for IκBα.
      Accumulating evidence reveals that tumorigenesis or oncogenesis is a multistep process and that these steps reflect defections in regulatory circuits that govern normal cell proliferation, differentiation, and death.
      • Hanahan D
      • Weinberg RA
      The hallmarks of cancer.
      Although abnormal activation or function of NF-κB has been clearly demonstrated in the initiation or facilitation of oncogenesis, the central question that has to be answered is: how many and what steps are influenced by NF-κB. NF-κB has been shown to antagonize the function of p53 as discussed earlier.
      • Wadgaonkar R
      • Phelps KM
      • Haque Z
      • Williams AJ
      • Silverman ES
      • Collins T
      CREB-binding protein is a nuclear integrator of nuclear factor-κB and p53 signaling.
      Obviously, this antagonism of p53 by NF-κB will result in the evasion of cells from stress-induced cell-cycle arrest and/or programmed cell death and consequently sensitize the cells for genomic instability. Furthermore, NF-κB could promote cell-cycle transition by a direct transcriptional up-regulation of the cyclin D1 gene.
      • Joyce D
      • Bouzahzah B
      • Fu M
      • Albanese C
      • D'Amico M
      • Steer J
      • Klein JU
      • Lee RJ
      • Segall JE
      • Westwick JK
      • Der CJ
      • Pestell RG
      Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-κB-dependent pathway.
      • Hinz M
      • Krappmann D
      • Eichten A
      • Heder A
      • Scheidereit C
      • Strauss M
      NF-κB function in growth control: regulation of cyclin D1 expression and G0/G1-to-S-phase transition.
      • Guttridge DC
      • Albanese C
      • Reuther JY
      • Pestell RG
      • Baldwin Jr, AS
      NF-κB controls cell growth and differentiation through transcriptional regulation of cyclin D1.
      • Biswas DK
      • Cruz AP
      • Gansberger E
      • Pardee AB
      Epidermal growth factor-induced nuclear factor κB activation: a major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells.
      Although it remains to be confirmed, this increased expression of cyclin D1 may possibly provide cells with an uncontrolled or limitless replicative potential. Up-regulation of anti-apoptotic genes, such as cIAP1, cIAP2, XIAP, and bcl-xl, by NF-κB,
      • Chen F
      • Castranova V
      • Shi X
      • Demers LM
      New insights into the role of nuclear factor-κB, a ubiquitous transcription factor in the initiation of diseases.
      is an additional mean of cells to escape from or resist signal-induced apoptosis. Other NF-κB-regulated genes include those encoding intercellular adhesion molecule-1,
      • Baldwin Jr, AS
      The NF-κB and IκB proteins: new discoveries and insights.
      extracellular matrix protein tenascin-C,
      • Mettouchi A
      • Cabon F
      • Montreau N
      • Dejong V
      • Vernier P
      • Gherzi R
      • Mercier G
      • Binetruy B
      The c-Jun-induced transformation process involves complex regulation of tenascin-C expression.
      vascular endothelial growth factor,
      • Mettouchi A
      • Cabon F
      • Montreau N
      • Dejong V
      • Vernier P
      • Gherzi R
      • Mercier G
      • Binetruy B
      The c-Jun-induced transformation process involves complex regulation of tenascin-C expression.
      chemokines, and cyclooxygenase-2.
      • Mettouchi A
      • Cabon F
      • Montreau N
      • Dejong V
      • Vernier P
      • Gherzi R
      • Mercier G
      • Binetruy B
      The c-Jun-induced transformation process involves complex regulation of tenascin-C expression.
      These gene products are directly associated with the tumor cell metastasis and tumor tissue angiogenesis.
      The key role that NF-κB plays on multiple steps of oncogenesis makes this factor a central and favorable target for therapeutic intervention of cancer, especially, certain types of leukemia or lymphomas.
      • Schwartz SA
      • Hernandez A
      • Mark Evers B
      The role of NF-κB/IκB proteins in cancer: implications for novel treatment strategies.
      Indeed, experimental data suggest that inhibition of NF-κB by antisense oligonucleotides to relA, degradation resistant IκB-α, and aspirin or nonsteroidal anti-inflammatory drugs, could enhance the efficacy of cancer chemotherapies and radiation.
      • Mayo MW
      • Baldwin AS
      The transcription factor NF-κB: control of oncogenesis and cancer therapy resistance.
      • Baldwin AS
      Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κB.
      Studies by Wang and co-workers
      • Wang CY
      • Mayo MW
      • Korneluk RG
      • Goeddel DV
      • Baldwin Jr, AS
      NF-κB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation.
      • Wang CY
      • Cusack JC
      • Liu R
      • Baldwin AS
      Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-κB.
      showed that inhibition of NF-κB by infecting the cells with an adenovirus carrying a modified form of IκB-α (superrepressor IκB-α) leads to dramatically enhanced apoptosis of HT1080 fibrosarcoma cells in response to ionizing radiation or daunorubicin treatment. Consistent with these reports, working with pancreatic cancer cell lines exposed to VP16 or doxorubicin, Arlt and colleagues
      • Arlt A
      • Vorndamm J
      • Breitenbroich M
      • Folsch UR
      • Kalthoff H
      • Schmidt WE
      • Schafer H
      Inhibition of the NF-κB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin.
      demonstrated recently that NF-κB inhibition by pharmacological proteasome inhibitors or transfection of the cells with a N-terminal-truncated IκB-α variant efficiently reduces chemoresistance of these cells. Using similar or different approaches to inhibit NF-κB, this effect has also been noted in a variety of other cell types including non-small cell lung cancers,
      • Jones DR
      • Broad RM
      • Madrid LV
      • Baldwin AS
      • Mayo MW
      Inhibition of NF-κB sensitizes non-small cell lung cancer cells to chemotherapy-induced apoptosis.
      head and neck squamous carcinomas,
      • Kato T
      • Duffey DC
      • Ondrey FG
      • Dong G
      • Chen Z
      • Cook JA
      • Mitchell JB
      • Van Waes C
      Cisplatin and radiation sensitivity in human head and neck squamous carcinomas are independently modulated by glutathione and transcription factor NF-κB.
      human myeloblastic leukemia cells,
      • Romano MF
      • Lamberti A
      • Bisogni R
      • Tassone P
      • Pagnini D
      • Storti G
      • Del Vecchio L
      • Turco MC
      • Venuta S
      Enhancement of cytosine arabinoside-induced apoptosis in human myeloblastic leukemia cells by NF-κB/Rel-specific decoy oligodeoxynucleotides.
      colorectal cancer,
      • Cusack JC
      • Liu R
      • Baldwin AS
      Inducible chemoresistance to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothe cin (CPT-11) in colorectal cancer cells and a xenograft model is overcome by inhibition of nuclear factor-κB activation.
      and bladder cancer cells.
      • Sumitomo M
      • Tachibana M
      • Ozu C
      • Asakura H
      • Murai M
      • Hayakawa M
      • Nakamura H
      • Takayanagi A
      • Shimizu N
      Induction of apoptosis of cytokine-producing bladder cancer cells by adenovirus-mediated IκBα overexpression.
      Despite these encouraging observations, however, care has to be taken when using different approaches to inhibit NF-κB that might be attributable to the process of oncogenesis. Indeed, different approaches for the inhibition of NF-κB does not necessarily lead to the same extents of inactivation of NF-κB because of the existence of functionally and stoichiometrically different NF-κB complexes that respond to different activation signals.
      • Baldwin Jr, AS
      The NF-κB and IκB proteins: new discoveries and insights.
      Also, the inhibitory effect of NF-κB inhibitors can vary considerably between different cell types because of unique simultaneous or asynchronous events triggered by these inhibitors in any given cell type.
      • Bours V
      • Bentires-Alj M
      • Hellin AC
      • Viatour P
      • Robe P
      • Delhalle S
      • Benoit V
      • Merville MP
      Nuclear factor-κB, cancer, and apoptosis.

      Summary

      The detailed molecular mechanisms by which the NF-κB transcription factor contributes to cell growth control, such as cell apoptosis, cell-cycle transition, and oncogenesis remain to be further determined. One of the major challenges in understanding mechanisms of cell growth regulation by NF-κB in response to environmental stress is to elucidate how signal transduction pathways are activated and how signaling cross-talk and specificity are achieved when several signaling pathways are activated simultaneously by stress inducers that elicit different cellular responses. For instance, why does activation of the NF-κB, an anti-apoptotic transcription factor, coincide with obvious apoptotic features in cells undergoing stress responses? Because many stress inducers and their mediators are highly reactive but nonspecific, an activation of only one specific signaling pathway is hard to achieve in the cells in response to a particular inducer. Even in a single signaling pathway, because of their highly reactive and nonspecific characteristics, certain stress inducers and their mediators can in principle induce conflicting signals by affecting signaling molecules at different levels. A good example is the effects of oxidative stress on NF-κB signaling pathway. It has been frequently observed in certain types of cells that oxidative stress amplified or potentiated NF-κB activation, whereas at the same time oxidation of IKK or NF-κB proteins inhibited NF-κB function. Translating the knowledge gained by studying the connections among NF-κB activation, cell apoptosis, cell-cycle regulation, and oncogenesis may aid in identifying novel preventive and therapeutic measures for diseases, such as chronic inflammation and cancer.

      Acknowledgements

      We thank our colleague Dr Murali Rao for helpful suggestions and critique of the manuscript; and to the many friends whose primary valuable work in the related fields we could not directly acknowledge because of space constrains. Dr. Fei Chen thanks the Health Effects Laboratory Division of National Institute for Occupational Safety and Health for support through a cooperative agreement from the Association of Teachers of Preventive Medicine and the Centers for Disease Control and Prevention of the United States.

      References

        • Zandi E
        • Karin M
        Bridging the gap: composition, regulation, and physiological function of the IκB kinase complex.
        Mol Cell Biol. 1999; 19: 4547-4551
        • Karin M
        • Ben-Neriah Y
        Phosphorylation meets ubiquitination: the control of NF-κB activity.
        Annu Rev Immunol. 2000; 18: 621-663
        • Israel A
        The IKK complex: an integrator of all signals that activate NF-κB?.
        Trends Cell Biol. 2000; 10: 129-133
        • Chen F
        • Castranova V
        • Shi X
        • Demers LM
        New insights into the role of nuclear factor-κB, a ubiquitous transcription factor in the initiation of diseases.
        Clin Chem. 1999; 45: 7-17
        • Baldwin Jr, AS
        The NF-κB and IκB proteins: new discoveries and insights.
        Annu Rev Immunol. 1996; 14: 649-683
        • Ghosh S
        • May MJ
        • Kopp EB
        NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses.
        Annu Rev Immunol. 1998; 16: 225-260
        • Siebenlist U
        • Franzoso G
        • Brown K
        Structure, regulation and function of NF-κB.
        Annu Rev Cell Biol. 1994; 10: 405-455
        • Pahl HL
        Activators and target genes of Rel/NF-κB transcription factors.
        Oncogene. 1999; 18: 6853-6866
        • Gilmore TD
        The Rel/NF-κB signal transduction pathway: introduction.
        Oncogene. 1999; 18: 6842-6844
        • Sun SC
        • Ballard DW
        Persistent activation of NF-κB by the tax transforming protein of HTLV-1: hijacking cellular IκB kinases.
        Oncogene. 1999; 18: 6948-6958
        • Neish AS
        • Gewirtz AT
        • Zeng H
        • Young AN
        • Hobert ME
        • Karmali V
        • Rao AS
        • Madara JL
        Prokaryotic regulation of epithelial responses by inhibition of IκBα ubiquitination.
        Science. 2000; 289: 1560-1563
        • Palombella VJ
        • Rando OJ
        • Goldberg AL
        • Maniatis T
        The ubiquitin-proteasome pathway is required for processing the NF-κB1 precursor protein and the activation of NF-κB.
        Cell. 1994; 78: 773-785
        • Woronicz JD
        • Gao X
        • Cao Z
        • Rothe M
        • Goeddel DV
        IκB kinase-β: NF-κB activation and complex formation with IκB kinase-α and NIK.
        Science. 1997; 278: 866-869
        • Mercurio F
        • Zhu H
        • Murray BW
        • Shevchenko A
        • Bennett BL
        • Li J
        • Young DB
        • Barbosa M
        • Mann M
        • Manning A
        • Rao A
        IKK-1 and IKK-2: cytokine-activated IκB kinases essential for NF-κB activation.
        Science. 1997; 278: 860-866
        • Cohen L
        • Henzel WJ
        • Baeuerle PA
        IKAP is a scaffold protein of the IκB kinase complex.
        Nature. 1998; 395: 292-296
        • Krappmann D
        • Hatada EN
        • Tegethoff S
        • Li J
        • Klippel A
        • Giese K
        • Baeuerle PA
        • Scheidereit C
        The IκB kinase (IKK) complex is tripartite and contains IKKγ but not IKAP as a regular component.
        J Biol Chem. 2000; 275: 29779-29787
        • Li X
        • Commane M
        • Nie H
        • Hua X
        • Chatterjee-Kishore M
        • Wald D
        • Haag M
        • Stark GR
        Act1, an NF-κB-activating protein.
        Proc Natl Acad Sci USA. 2000; 97: 10489-10493
        • Leonardi A
        • Chariot A
        • Claudio E
        • Cunningham K
        • Siebenlist U
        CIKS, a connection to IκB kinase and stress-activated protein kinase.
        Proc Natl Acad Sci USA. 2000; 97: 10494-10499
        • Tojima Y
        • Fujimoto A
        • Delhase M
        • Chen Y
        • Hatakeyama S
        • Nakayama K
        • Kaneko Y
        • Nimura Y
        • Motoyama N
        • Ikeda K
        • Karin M
        • Nakanishi M
        NAK is an IκB kinase-activating kinase.
        Nature. 2000; 404: 778-782
        • Huang S
        • DeGuzman A
        • Bucana CD
        • Fidler IJ
        Nuclear factor-κB activity correlates with growth, angiogenesis, and metastasis of human melanoma cells in nude mice.
        Clin Cancer Res. 2000; 6: 2573-2581
        • Strasser A
        • O'Connor L
        • Dixit VM
        Apoptosis signaling.
        Annu Rev Biochem. 2000; 69: 217-245
        • Ashkenazi A
        • Dixit VM
        Death receptors: signaling and modulation.
        Science. 1998; 281: 1305-1308
        • Green DR
        • Reed JC
        Mitochondria and apoptosis.
        Science. 1998; 281: 1309-1312
        • De Laurenzi V
        • Melino G
        Apoptosis. The little devil of death.
        Nature. 2000; 406: 135-136
        • Du C
        • Fang M
        • Li Y
        • Li L
        • Wang X
        Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition.
        Cell. 2000; 102: 33-42
        • Verhagen AM
        • Ekert PG
        • Pakusch M
        • Silke J
        • Connolly LM
        • Reid GE
        • Moritz RL
        • Simpson RJ
        • Vaux DL
        Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins.
        Cell. 2000; 102: 43-53
        • Susin SA
        • Lorenzo HK
        • Zamzami N
        • Marzo I
        • Snow BE
        • Brothers GM
        • Mangion J
        • Jacotot E
        • Costantini P
        • Loeffler M
        • Larochette N
        • Goodlett DR
        • Aebersold R
        • Siderovski DP
        • Penninger JM
        • Kroemer G
        Molecular characterization of mitochondrial apoptosis-inducing factor.
        Nature. 1999; 397: 441-446
        • LaCasse EC
        • Baird S
        • Korneluk RG
        • MacKenzie AE
        The inhibitors of apoptosis (IAPs) and their emerging role in cancer.
        Oncogene. 1998; 17: 3247-3259
        • Reed JC
        Bcl-2 family proteins.
        Oncogene. 1998; 17: 3225-3236
        • Dahl AM
        • Klein C
        • Andres PG
        • London CA
        • Lodge MP
        • Mulligan RC
        • Abbas AK
        Expression of bcl-X(L) restores cell survival, but not proliferation off effector differentiation, in CD28-deficient T lymphocytes.
        J Exp Med. 2000; 191: 2031-2038
        • Polyak K
        • Xia Y
        • Zweier JL
        • Kinzler KW
        • Vogelstein B
        A model for p53-induced apoptosis.
        Nature. 1997; 389: 300-305
        • Amundson SA
        • Myers TG
        • Fornace Jr, AJ
        Roles for p53 in growth arrest and apoptosis: putting on the brakes after genotoxic stress.
        Oncogene. 1998; 17: 3287-3299
        • Gu Z
        • Flemington C
        • Chittenden T
        • Zambetti GP
        ei24, a p53 response gene involved in growth suppression and apoptosis.
        Mol Cell Biol. 2000; 20: 233-241
        • Oda E
        • Ohki R
        • Murasawa H
        • Nemoto J
        • Shibue T
        • Yamashita T
        • Tokino T
        • Taniguchi T
        • Tanaka N
        Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis.
        Science. 2000; 288: 1053-1058
        • Barkett M
        • Gilmore TD
        Control of apoptosis by Rel/NF-κB transcription factors.
        Oncogene. 1999; 18: 6910-6924
        • Aggarwal BB
        Apoptosis and nuclear factor-κB: a tale of association and dissociation.
        Biochem Pharmacol. 2000; 60: 1033-1039
        • Hsu SC
        • Gavrilin MA
        • Lee HH
        • Wu CC
        • Han SH
        • Lai MZ
        NF-κB-dependent Fas ligand expression.
        Eur J Immunol. 1999; 29: 2948-2956
        • Matsui K
        • Fine A
        • Zhu B
        • Marshak-Rothstein A
        • Ju ST
        Identification of two NF-κB sites in mouse CD95 ligand (Fas ligand) promoter: functional analysis in T cell hybridoma.
        J Immunol. 1998; 161: 3469-3473
        • Beg AA
        • Sha WC
        • Bronson RT
        • Ghosh S
        • Baltimore D
        Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB.
        Nature. 1995; 376: 167-170
        • Li ZW
        • Chu W
        • Hu Y
        • Delhase M
        • Deerinck T
        • Ellisman M
        • Johnson R
        • Karin M
        The IKKβ subunit of IκB kinase (IKK) is essential for nuclear factor κB activation and prevention of apoptosis.
        J Exp Med. 1999; 189: 1839-1845
        • Tanaka M
        • Fuentes ME
        • Yamaguchi K
        • Durnin MH
        • Dalrymple SA
        • Hardy KL
        • Goeddel DV
        Embryonic lethality, liver degeneration, and impaired NF-κB activation in IKK-β-deficient mice.
        Immunity. 1999; 10: 421-429
        • Li Q
        • Estepa G
        • Memet S
        • Israel A
        • Verma IM
        Complete lack of NF-κB activity in IKK1 and IKK2 double-deficient mice: additional defect in neurulation.
        Genes Dev. 2000; 14: 1729-1733
        • Gerondakis S
        • Grossmann M
        • Nakamura Y
        • Pohl T
        • Grumont R
        Genetic approaches in mice to understand Rel/NF-κB and IκB function: transgenics and knockouts.
        Oncogene. 1999; 18: 6888-6895
        • Makris C
        • Godfrey VL
        • Krahn-Senftleben G
        • Takahashi T
        • Roberts JL
        • Schwarz T
        • Feng L
        • Johnson RS
        • Karin M
        Female mice heterozygous for IKKγ/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti.
        Mol Cell. 2000; 5: 969-979
        • Schmidt-Supprian M
        • Bloch W
        • Courtois G
        • Addicks K
        • Israel A
        • Rajewsky K
        • Pasparakis M
        NEMO/IKKγ-deficient mice model incontinentia pigmenti.
        Mol Cell. 2000; 5: 981-992
        • Rosenfeld ME
        • Prichard L
        • Shiojiri N
        • Fausto N
        Prevention of hepatic apoptosis and embryonic lethality in RelA/TNFR-1 double knockout mice.
        Am J Pathol. 2000; 156: 997-1007
        • Doi TS
        • Marino MW
        • Takahashi T
        • Yoshida T
        • Sakakura T
        • Old LJ
        • Obata Y
        Absence of tumor necrosis factor rescues RelA-deficient mice from embryonic lethality.
        Proc Natl Acad Sci USA. 1999; 96: 2994-2999
        • Li Q
        • Van Antwerp D
        • Mercurio F
        • Lee KF
        • Verma IM
        Severe liver degeneration in mice lacking the IkB kinase 2 gene.
        Science. 1999; 284: 321-325
        • Fausto N
        • Laird AD
        • Webber EM
        Liver regeneration. 2. Role of growth factors and cytokines in hepatic regeneration.
        FASEB J. 1995; 9: 1527-1536
        • Joyce D
        • Bouzahzah B
        • Fu M
        • Albanese C
        • D'Amico M
        • Steer J
        • Klein JU
        • Lee RJ
        • Segall JE
        • Westwick JK
        • Der CJ
        • Pestell RG
        Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-κB-dependent pathway.
        J Biol Chem. 1999; 274: 25245-25249
        • Hinz M
        • Krappmann D
        • Eichten A
        • Heder A
        • Scheidereit C
        • Strauss M
        NF-κB function in growth control: regulation of cyclin D1 expression and G0/G1-to-S-phase transition.
        Mol Cell Biol. 1999; 19: 2690-2698
        • Guttridge DC
        • Albanese C
        • Reuther JY
        • Pestell RG
        • Baldwin Jr, AS
        NF-κB controls cell growth and differentiation through transcriptional regulation of cyclin D1.
        Mol Cell Biol. 1999; 19: 5785-5799
        • Chen F
        • Demers LM
        • Vallyathan V
        • Lu Y
        • Castranova V
        • Shi X
        Involvement of 5′-flanking κB-like sites within bcl-x gene in silica-induced Bcl-x expression.
        J Biol Chem. 1999; 274: 35591-35595
        • Chen C
        • Edelstein LC
        • Gelinas C
        The Rel/NF-κB family directly activates expression of the apoptosis inhibitor Bcl-x(L).
        Mol Cell Biol. 2000; 20: 2687-2695
        • Wang CY
        • Mayo MW
        • Korneluk RG
        • Goeddel DV
        • Baldwin Jr, AS
        NF-κB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation.
        Science. 1998; 281: 1680-1683
        • Ivanov VN
        • Lee RK
        • Podack ER
        • Malek TR
        Regulation of Fas-dependent activation-induced T cell apoptosis by cAMP signaling: a potential role for transcription factor NF-κB.
        Oncogene. 1997; 14: 2455-2464
        • Kasibhatla S
        • Brunner T
        • Genestier L
        • Echeverri F
        • Mahboubi A
        • Green DR
        DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF-κB and AP-1.
        Mol Cell. 1998; 1: 543-551
        • Rivera-Walsh I
        • Cvijic ME
        • Xiao G
        • Sun SC
        The NF-κB signaling pathway is not required for Fas ligand gene induction but mediates protection from activation-induced cell death.
        J Biol Chem. 2000; 275: 25222-25230
        • Latinis KM
        • Norian LA
        • Eliason SL
        • Koretzky GA
        Two NFAT transcription factor binding sites participate in the regulation of CD95 (Fas) ligand expression in activated human T cells.
        J Biol Chem. 1997; 272: 31427-31434
        • Bales KR
        • Du Y
        • Dodel RC
        • Yan GM
        • Hamilton-Byrd E
        • Paul SM
        The NF-κB/Rel family of proteins mediates Ab-induced neurotoxicity and glial activation.
        Brain Res Mol Brain Res. 1998; 57: 63-72
        • Guo Q
        • Robinson N
        • Mattson MP
        Secreted b-amyloid precursor protein counteracts the proapoptotic action of mutant presenilin-1 by activation of NF-κB and stabilization of calcium homeostasis.
        J Biol Chem. 1998; 273: 12341-12351
        • Yu Z
        • Zhou D
        • Bruce-Keller AJ
        • Kindy MS
        • Mattson MP
        Lack of the p50 subunit of nuclear factor-κB increases the vulnerability of hippocampal neurons to excitotoxic injury.
        J Neurosci. 1999; 19: 8856-8865
        • Mattson MP
        • Camandola S
        NF-κB in neuronal plasticity and neurodegenerative disorders.
        J Clin Invest. 2001; 107: 247-254
        • Yang JP
        • Hori M
        • Takahashi N
        • Kawabe T
        • Kato H
        • Okamoto T
        NF-κB subunit p65 binds to 53BP2 and inhibits cell death induced by 53BP2.
        Oncogene. 1999; 18: 5177-5186
        • Wadgaonkar R
        • Phelps KM
        • Haque Z
        • Williams AJ
        • Silverman ES
        • Collins T
        CREB-binding protein is a nuclear integrator of nuclear factor-κB and p53 signaling.
        J Biol Chem. 1999; 274: 1879-1882
        • Shao J
        • Fujiwara T
        • Kadowaki Y
        • Fukazawa T
        • Waku T
        • Itoshima T
        • Yamatsuji T
        • Nishizaki M
        • Roth JA
        • Tanaka N
        Overexpression of the wild-type p53 gene inhibits NF-κB activity and synergizes with aspirin to induce apoptosis in human colon cancer cells.
        Oncogene. 2000; 19: 726-736
        • Ariumi Y
        • Kaida A
        • Lin JY
        • Hirota M
        • Masui O
        • Yamaoka S
        • Taya Y
        • Shimotohno K
        HTLV-1 tax oncoprotein represses the p53-mediated trans-activation function through coactivator CBP sequestration.
        Oncogene. 2000; 19: 1491-1499
        • Pise-Masison CA
        • Mahieux R
        • Jiang H
        • Ashcroft M
        • Radonovich M
        • Duvall J
        • Guillerm C
        • Brady JN
        Inactivation of p53 by human T-cell lymphotropic virus type 1 Tax requires activation of the NF-κB pathway and is dependent on p53 phosphorylation.
        Mol Cell Biol. 2000; 20: 3377-3386
        • Ikeda A
        • Sun X
        • Li Y
        • Zhang Y
        • Eckner R
        • Doi TS
        • Takahashi T
        • Obata Y
        • Yoshioka K
        • Yamamoto K
        p300/CBP-dependent and -independent transcriptional interference between NF-κB RelA and p53.
        Biochem Biophys Res Commun. 2000; 272: 375-379
        • Jung M
        • Kondratyev A
        • Lee SA
        • Dimtchev A
        • Dritschilo A
        ATM gene product phosphorylates IκB-α.
        Cancer Res. 1997; 57: 24-27
        • Ashburner BP
        • Shackelford RE
        • Baldwin Jr, AS
        • Paules RS
        Lack of involvement of ataxia telangiectasia mutated (ATM) in regulation of nuclear factor-kB (NF-kB) in human diploid fibroblasts.
        Cancer Res. 1999; 59: 5456-5460
        • Liu L
        • Kwak YT
        • Bex F
        • Garcia-Martinez LF
        • Li XH
        • Meek K
        • Lane WS
        • Gaynor RB
        DNA-dependent protein kinase phosphorylation of IκBα and IκBβ regulates NF-κB DNA binding properties.
        Mol Cell Biol. 1998; 18: 4221-4234
        • Ryan KM
        • Ernst MK
        • Rice NR
        • Vousden KH
        Role of NF-κB in p53-mediated programmed cell death.
        Nature. 2000; 404: 892-897
        • Perkins ND
        • Felzien LK
        • Betts JC
        • Leung K
        • Beach DH
        • Nabel GJ
        Regulation of NF-κB by cyclin-dependent kinases associated with the p300 coactivator.
        Science. 1997; 275: 523-527
        • Levkau B
        • Scatena M
        • Giachelli CM
        • Ross R
        • Raines EW
        Apoptosis overrides survival signals through a caspase-mediated dominant-negative NF-κB loop.
        Nat Cell Biol. 1999; 1: 227-233
        • Barkett M
        • Xue D
        • Horvitz HR
        • Gilmore TD
        Phosphorylation of IκBα inhibits its cleavage by caspase CPP32 in vitro.
        J Biol Chem. 1997; 272: 29419-29422
        • Reuther JY
        • Baldwin Jr, AS
        Apoptosis promotes a caspase-induced amino-terminal truncation of IκBα that functions as a stable inhibitor of NF-κB.
        J Biol Chem. 1999; 274: 20664-20670
        • Jung M
        • Zhang Y
        • Dimtchev A
        • Dritschilo A
        Impaired regulation of nuclear factor-κB results in apoptosis induced by γ radiation.
        Radiat Res. 1998; 149: 596-601
        • Silverman N
        • Zhou R
        • Stoven S
        • Pandey N
        • Hultmark D
        • Maniatis T
        A drosophila IκB kinase complex required for relish cleavage and antibacterial immunity.
        Genes Dev. 2000; 14: 2461-2471
        • Chaudhary PM
        • Eby MT
        • Jasmin A
        • Kumar A
        • Liu L
        • Hood L
        Activation of the NF-κB pathway by caspase 8 and its homologs.
        Oncogene. 2000; 19: 4451-4460
        • Ogura Y
        • Inohara N
        • Benito A
        • Chen FF
        • Yamaoka S
        • Nunez G
        Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-κB.
        J Biol Chem. 2000; 276: 4812-4818
        • Ruland J
        • Duncan GS
        • Elia A
        • del Barco Barrantes I
        • Nguyen L
        • Plyte S
        • Millar DG
        • Bouchard D
        • Wakeham A
        • Ohashi PS
        • Mak TW
        Bcl10 is a positive regulator of antigen receptor-induced activation of NF-κB and neural tube closure.
        Cell. 2001; 104: 33-42
        • Poyet JL
        • Srinivasula SM
        • Alnemri ES
        vCLAP, a caspase recruitment domain-containing protein of equine herpesvirus-2, persistently activates the IκB kinases through oligomerization of IKKγ.
        J Biol Chem. 2001; 276: 3183-3187
        • Nurse P
        A long twentieth century of the cell cycle and beyond.
        Cell. 2000; 100: 71-78
        • Shackelford RE
        • Kaufmann WK
        • Paules RS
        Cell cycle control, checkpoint mechanisms, and genotoxic stress.
        Environ Health Perspect. 1999; 107: S5-S24
        • Sheikh MS
        • Hollander MC
        • Fornance Jr, AJ
        Role of Gadd45 in apoptosis.
        Biochem Pharmacol. 2000; 59: 43-45
        • Sandor V
        • Senderowicz A
        • Mertins S
        • Sackett D
        • Sausville E
        • Blagosklonny MV
        • Bates SE
        P21-dependent g(1)arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228.
        Br J Cancer. 2000; 83: 817-825
        • Jimenez GS
        • Khan SH
        • Stommel JM
        • Wahl GM
        p53 regulation by post-translational modification and nuclear retention in response to diverse stresses.
        Oncogene. 1999; 18: 7656-7665
        • Graves PR
        • Yu L
        • Schwarz JK
        • Gales J
        • Sausville EA
        • O'Connor PM
        • Piwnica-Worms H
        The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01.
        J Biol Chem. 2000; 275: 5600-5605
        • Hutchins JR
        • Hughes M
        • Clarke PR
        Substrate specificity determinants of the checkpoint protein kinase Chk1.
        FEBS Lett. 2000; 466: 91-95
        • Baldwin Jr, AS
        • Azizkhan JC
        • Jensen DE
        • Beg AA
        • Coodly LR
        Induction of NF-κB DNA-binding activity during the G0-to-G1 transition in mouse fibroblasts.
        Mol Cell Biol. 1991; 11: 4943-4951
        • Cressman DE
        • Greenbaum LE
        • Haber BA
        • Taub R
        Rapid activation of post-hepatectomy factor/nuclear factor κB in hepatocytes, a primary response in the regenerating liver.
        J Biol Chem. 1994; 269: 30429-30435
        • Duckett CS
        • Perkins ND
        • Leung K
        • Agranoff AB
        • Nabel GJ
        Cytokine induction of nuclear factor κB in cycling and growth-arrested cells. Evidence for cell cycle-independent activation.
        J Biol Chem. 1995; 270: 18836-18840
        • Yamada Y
        • Kirillova I
        • Peschon JJ
        • Fausto N
        Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor.
        Proc Natl Acad Sci USA. 1997; 94: 1441-1446
        • Biswas DK
        • Cruz AP
        • Gansberger E
        • Pardee AB
        Epidermal growth factor-induced nuclear factor κB activation: a major pathway of cell-cycle progression in estrogen-receptor negative breast cancer cells.
        Proc Natl Acad Sci USA. 2000; 97: 8542-8547
        • Bash J
        • Zong WX
        • Gelinas C
        c-Rel arrests the proliferation of HeLa cells and affects critical regulators of the G1/S-phase transition.
        Mol Cell Biol. 1997; 17: 6526-6536
        • Otsuka G
        • Nagaya T
        • Saito K
        • Mizuno M
        • Yoshida J
        • Seo H
        Inhibition of nuclear factor-κB activation confers sensitivity to tumor necrosis factor-a by impairment of cell cycle progression in human glioma cells.
        Cancer Res. 1999; 59: 4446-4452
        • Kaltschmidt B
        • Kaltschmidt C
        • Hehner SP
        • Droge W
        • Schmitz ML
        Repression of NF-κB impairs HeLa cell proliferation by functional interference with cell cycle checkpoint regulators.
        Oncogene. 1999; 18: 3213-3225
        • Nevins JR
        E2F: a link between the Rb tumor suppressor protein and viral oncoproteins.
        Science. 1992; 258: 424-429
        • Sherr CJ
        • Roberts JM
        Inhibitors of mammalian G1 cyclin-dependent kinases.
        Genes Dev. 1995; 9: 1149-1163
        • Weinberg RA
        The retinoblastoma protein and cell cycle control.
        Cell. 1995; 81: 323-330
        • Sheehy AM
        • Schlissel MS
        Overexpression of RelA causes G1 arrest and apoptosis in a pro-B cell line.
        J Biol Chem. 1999; 274: 8708-8716
        • Takeda K
        • Takeuchi O
        • Tsujimura T
        • Itami S
        • Adachi O
        • Kawai T
        • Sanjo H
        • Yoshikawa K
        • Terada N
        • Akira S
        Limb and skin abnormalities in mice lacking IKKα.
        Science. 1999; 284: 313-316
        • Hu Y
        • Baud V
        • Delhase M
        • Zhang P
        • Deerinck T
        • Ellisman M
        • Johnson R
        • Karin M
        Abnormal morphogenesis but intact IKK activation in mice lacking the IKKα subunit of IκB kinase.
        Science. 1999; 284: 316-320
        • Chen F
        • Lu Y
        • Zhang Z
        • Vallyathan V
        • Ding M
        • Castranova V
        • Shi X
        Opposite effect of NF-κB and c-Jun-N-terminal kinase on p53-independent GADD45 induction by arsenite.
        J Biol Chem. 2001; 276: 11414-11419
        • Sovak MA
        • Bellas RE
        • Kim DW
        • Zanieski GJ
        • Rogers AE
        • Traish AM
        • Sonenshein GE
        Aberrant nuclear factor-κB/Rel expression and the pathogenesis of breast cancer.
        J Clin Invest. 1997; 100: 2952-2960
        • Mukhopadhyay T
        • Roth JA
        • Maxwell SA
        Altered expression of the p50 subunit of the NF-κB transcription factor complex in non-small cell lung carcinoma.
        Oncogene. 1995; 11: 999-1003
        • Gilmore TD
        • Koedood M
        • Piffat KA
        • White DW
        Rel/NF-κB/IκB proteins and cancer.
        Oncogene. 1996; 13: 1367-1378
        • Bargou RC
        • Leng C
        • Krappmann D
        • Emmerich F
        • Mapara MY
        • Bommert K
        • Royer HD
        • Scheidereit C
        • Dorken B
        High-level nuclear NF-κB and Oct-2 is a common feature of cultured Hodgkin/Reed-Sternberg cells.
        Blood. 1996; 87: 4340-4347
        • Devalaraja MN
        • Wang DZ
        • Ballard DW
        • Richmond A
        Elevated constitutive IκB kinase activity and IκBα phosphorylation in Hs294T melanoma cells lead to increased basal MGSA/GRO-α transcription.
        Cancer Res. 1999; 59: 1372-1377
        • Dejardin E
        • Deregowski V
        • Chapelier M
        • Jacobs N
        • Gielen J
        • Merville MP
        • Bours V
        Regulation of NF-κB activity by IκB-related proteins in adenocarcinoma cells.
        Oncogene. 1999; 18: 2567-2577
        • Sumitomo M
        • Tachibana M
        • Ozu C
        • Asakura H
        • Murai M
        • Hayakawa M
        • Nakamura H
        • Takayanagi A
        • Shimizu N
        Induction of apoptosis of cytokine-producing bladder cancer cells by adenovirus-mediated IκBα overexpression.
        Hum Gene Ther. 1999; 10: 37-47
        • Miwa M
        • Kushida S
        • Maeda N
        • Fang J
        • Kawamura T
        • Kameyama T
        • Uchida K
        Pathogenesis and prevention of HTLV-1-associated diseases.
        Leukemia. 1997; 11: S65-S66
        • Berger C
        • Brousset P
        • McQuain C
        • Knecht H
        Deletion variants within the NF-κB activation domain of the LMP1 oncogene in acquired immunodeficiency syndrome-related large cell lymphomas, in prelymphomas and atypical lymphoproliferations.
        Leuk Lymphoma. 1997; 26: 239-250
        • Nasti G
        • Vaccher E
        • Errante D
        • Tirelli U
        Malignant tumors and AIDS.
        Biomed Pharmacother. 1997; 51: 243-251
        • Carrasco D
        • Rizzo CA
        • Dorfman K
        • Bravo R
        The v-rel oncogene promotes malignant T-cell leukemia/lymphoma in transgenic mice.
        EMBO J. 1996; 15: 3640-3650
        • Neri A
        • Chang CC
        • Lombardi L
        • Salina M
        • Corradini P
        • Maiolo AT
        • Chaganti RS
        • Dalla-Favera R
        B cell lymphoma-associated chromosomal translocation involves candidate oncogene lyt-10, homologous to NF-κB p50.
        Cell. 1991; 67: 1075-1087
        • Fracchiolla NS
        • Lombardi L
        • Salina M
        • Migliazza A
        • Baldini L
        • Berti E
        • Cro L
        • Polli E
        • Maiolo AT
        • Neri A
        Structural alterations of the NF-κB transcription factor lyt-10 in lymphoid malignancies.
        Oncogene. 1993; 8: 2839-2845
        • Liptay S
        • Seriu T
        • Bartram CR
        • Schmid RM
        Germline configuration of nfkb2, c-rel and bcl3 in childhood acute lymphoblastic leukemia (ALL).
        Leukemia. 1997; 11: 1364-1366
        • Houldsworth J
        • Mathew S
        • Rao PH
        • Dyomina K
        • Louie DC
        • Parsa N
        • Offit K
        • Chaganti RS
        REL proto-oncogene is frequently amplified in extranodal diffuse large cell lymphoma.
        Blood. 1996; 87: 25-29
        • Michaux L
        • Dierlamm J
        • Wlodarska I
        • Bours V
        • Van den Berghe H
        • Hagemeijer A
        t(14;19)/BCL3 rearrangements in lymphoproliferative disorders: a review of 23 cases.
        Cancer Genet Cytogenet. 1997; 94: 36-43
        • Cabannes E
        • Khan G
        • Aillet F
        • Jarrett RF
        • Hay RT
        Mutations in the IκBα gene in Hodgkin's disease suggest a tumour suppressor role for IκBα.
        Oncogene. 1999; 18: 3063-3070
        • Hanahan D
        • Weinberg RA
        The hallmarks of cancer.
        Cell. 2000; 100: 57-70
        • Mettouchi A
        • Cabon F
        • Montreau N
        • Dejong V
        • Vernier P
        • Gherzi R
        • Mercier G
        • Binetruy B
        The c-Jun-induced transformation process involves complex regulation of tenascin-C expression.
        Mol Cell Biol. 1997; 17: 3202-3209
        • Schwartz SA
        • Hernandez A
        • Mark Evers B
        The role of NF-κB/IκB proteins in cancer: implications for novel treatment strategies.
        Surg Oncol. 1999; 8: 143-153
        • Mayo MW
        • Baldwin AS
        The transcription factor NF-κB: control of oncogenesis and cancer therapy resistance.
        Biochim Biophys Acta. 2000; 1470: M55-M62
        • Baldwin AS
        Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κB.
        J Clin Invest. 2001; 107: 241-246
        • Wang CY
        • Cusack JC
        • Liu R
        • Baldwin AS
        Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-κB.
        Nat Med. 1999; 5: 412-417
        • Arlt A
        • Vorndamm J
        • Breitenbroich M
        • Folsch UR
        • Kalthoff H
        • Schmidt WE
        • Schafer H
        Inhibition of the NF-κB sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin.
        Oncogene. 2001; 20: 859-868
        • Jones DR
        • Broad RM
        • Madrid LV
        • Baldwin AS
        • Mayo MW
        Inhibition of NF-κB sensitizes non-small cell lung cancer cells to chemotherapy-induced apoptosis.
        Ann Thorac Surg. 2000; 70: 930-937
        • Kato T
        • Duffey DC
        • Ondrey FG
        • Dong G
        • Chen Z
        • Cook JA
        • Mitchell JB
        • Van Waes C
        Cisplatin and radiation sensitivity in human head and neck squamous carcinomas are independently modulated by glutathione and transcription factor NF-κB.
        Head Neck. 2000; 22: 748-759
        • Romano MF
        • Lamberti A
        • Bisogni R
        • Tassone P
        • Pagnini D
        • Storti G
        • Del Vecchio L
        • Turco MC
        • Venuta S
        Enhancement of cytosine arabinoside-induced apoptosis in human myeloblastic leukemia cells by NF-κB/Rel-specific decoy oligodeoxynucleotides.
        Gene Ther. 2000; 7: 1234-1237
        • Cusack JC
        • Liu R
        • Baldwin AS
        Inducible chemoresistance to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothe cin (CPT-11) in colorectal cancer cells and a xenograft model is overcome by inhibition of nuclear factor-κB activation.
        Cancer Res. 2000; 60: 2323-2330
        • Bours V
        • Bentires-Alj M
        • Hellin AC
        • Viatour P
        • Robe P
        • Delhalle S
        • Benoit V
        • Merville MP
        Nuclear factor-κB, cancer, and apoptosis.
        Biochem Pharmacol. 2000; 60: 1085-1089