| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
From the Division of Endocrinology, Diabetes, and
Metabolism,*
Departments of Medicine, Biological Chemistry
and Pharmacology, University of California, Irvine, California; the
Department of Visceral and Transplantation
Surgery,
University of Bern, Bern,
Switzerland; and the Preuss Laboratory,
Department of Neurological Surgery, University of California, San
Francisco, California
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Id genes encode a family of four HLH proteins that lack the basic DNA binding domain.1,10 They act as dominant-negative HLH proteins by forming high affinity heterodimers with other bHLH proteins, thereby preventing them from binding to DNA and inhibiting transcription of differentiation-associated genes.10-12 Id gene expression is down-regulated on differentiation in many cell types in vitro and in vivo.13-18 In addition, Id proteins seem to be required for cell cycle progression through G1/S phase in certain cell types, and interaction between Id-2 and pRB is associated with enhanced proliferation in some cell lines in vitro.19-23
Pancreatic cancer is the fifth leading cause of cancer death in the United States, with a mortality rate that virtually equals its incidence rate.24 This malignancy is often associated with the overexpression of a variety of mitogenic growth factors and their receptors, and by oncogenic mutations of K-ras and inactivation of the p53 tumor suppressor gene.25 We have recently reported that pancreatic cancers overexpress the HLH protein Id-2, and that enhanced expression of this protein is evident in the cytoplasm of the cancer cells within the pancreatic tumor mass.26 It is not known, however, whether the expression of other Id proteins is altered in this malignancy, or whether their expression is altered in chronic pancreatitis (CP), an inflammatory disease that is characterized by dysplastic ducts, foci of proliferating ductal cells, acinar cell degeneration, and fibrosis.27 We now report that there is a five- to sixfold increase in Id-1 and Id-2 mRNA levels and a twofold increase in Id-3 mRNA levels in pancreatic cancer by comparison with the normal pancreas. In contrast, overall Id mRNA levels are not increased in CP.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Northern Blot Analysis
Northern blot analysis was carried out as described previously.26,28 Briefly, total RNA was extracted by the single step acid guanidinium thiocyanate phenol chloroform method. RNA was size-fractionated on 1.2% agarose/1.8 mol/L formaldehyde gels, electrotransferred onto nylon membranes, and cross-linked by UV irradiation. Blots were prehybridized and hybridized with cDNA probes and washed under high stringency conditions. The following cDNA probes were used: a 979-bp human Id-1 cDNA probe, a 440-bp human Id-2 cDNA probe, and a 450-bp human Id-3 cDNA probe, covering the entire coding regions of Id-1, Id-2, and Id-3, respectively. A BamHI 190-bp fragment of mouse 7S cDNA that hybridizes with human cytoplasmic RNA was used to confirm equal RNA loading and transfer. Blots were then exposed at -80°C to Kodak BioMax-MS films and the resulting autoradiographs were scanned to quantify the intensity of the radiographic bands.26,28 For each sample the ratio of Id mRNA expression to 7S expression was calculated. To compare the relative increase in expression of the respective Id mRNA species in the cancer and CP samples, the same normal samples were used for normal/cancer and normal/CP membranes. The median score for Id-1, Id-2, and Id-3 mRNA levels in these normal samples was set to 100. Statistical analysis was performed with SigmaStat software (Jandel Scientific, San Raphael, CA). The rank sum test was used, and P < 0.05 was taken as the level of significance.
Cell Culture and Western Blot Analysis
PANC-1, MIA-PaCa-2, ASPC-1, and CAPAN-1 human pancreatic cell lines were obtained from ATCC (Manassas, VA). COLO-357 human pancreatic cells were a gift from Dr. R. S. Metzger (Durham, NC). Cells were routinely grown in DMEM (COLO-357, MIA-PaCa-2, PANC-1) or RPMI (ASPC-1, CAPAN-1) supplemented with 10% fetal bovine serum, 100 U/ml penicillin, and 100 µg/ml streptomycin. For immunoblot analysis, exponentially growing cells (60–70% confluent) were solubilized in lysis buffer containing 50 mmol/L Tris-HCl, pH 7.4, 150 mmol/L NaCl, 1 mmol/L EDTA, 1 µg/ml pepstatin A, 1 mmol/L phenylmethylsulfonyl fluoride (PMSF), and 1% Triton X-100. Proteins were subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), transferred to Immobilon P membranes, and incubated for 90 minutes with the indicated antibodies and for 60 minutes with secondary antibodies against rabbit IgG. Visualization was performed by enhanced chemiluminescence.
Immunohistochemistry
Specific rabbit anti-human Id-1 (C-20), Id-2 (C-20), and Id-3 (C-20; all from Santa Cruz Biotechnology, Santa Cruz, CA) polyclonal antibodies were used for immunhistochemistry. These affinity-purified rabbit polyclonal antibodies specifically react with Id-1, Id-2, and Id-3, respectively, of human origin, as determined by Western blotting. Paraffin-embedded sections (4 µm) were subjected to immunostaining using the streptavidin-peroxidase technique. Where indicated, immunostaining for all three Id proteins was performed on serial sections. Endogenous peroxidase activity was blocked by incubation for 30 minutes with 0.3% hydrogen peroxide in methanol. Tissue sections were incubated for 15 minutes (23°C) with 10% normal goat serum and then incubated for 16 hours at 4°C with the indicated antibodies in PBS containing 1% bovine serum albumin. Bound antibodies were detected with biotinylated goat anti-rabbit IgG secondary antibodies and streptavidin-peroxidase complex, using diaminobenzidine tetrahydrochloride as the substrate. Sections were counterstained with Mayer's hematoxylin. Preabsorption with Id-1-, Id-2-, or Id-3-specific blocking peptides completely abolished immunoreactivity of the respective primary antibody. The immunohistochemical results were semiquantitatively analyzed as described previously.29,30 The percentage of positive cancer cells was stratified into four groups: 0, no cancer cells exhibiting immunoreactivity; 1, <33% of the cancer cells exhibiting immunoreactivity; 2, 33 to 67% of the cancer cells exhibiting immunoreactivity; 3 >67% of the cancer cells exhibiting immunoreactivity. The intensity of the immunohistochemical signal was also stratified into four groups: 0, no immunoreactivity; 1, weak immunoreactivity; 2, moderate immunoreactivity; 3, strong immunoreactivity. Finally, the sum of the results of the cell score and the intensity score was calculated. Statistical analysis was performed with SigmaStat software. The rank sum test was used, and P < 0.05 was taken as the level of significance.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
. In the cancer tissues,
Id-1 mRNA levels were elevated in 8 of 16 samples, Id-2 mRNA levels
were elevated in 9 of these samples, and Id-3 mRNA levels were elevated
in 6 of these samples (Figure 1A, 2)
. Concomitant overexpression of all
three Id species was observed in 6 of the cancer samples (38%). In
contrast, none of the Id mRNA species were overexpressed in CP by
comparison with normal controls (Figure 1B, 2)
. Densitometric analysis
of all of the autoradiograms indicated that there was a 6.5-fold
increase (P < 0.01) in Id-1 mRNA levels, a
fivefold increase (P < 0.01) in Id-2 mRNA
levels, and a twofold increase (P = 0.027) in
Id-3 mRNA levels in the pancreatic cancer samples in comparison to
normal controls (Figure 2)
. In contrast,
there was no statistically significant difference in the expression
levels of Id-1, Id-2, and Id-3, in CP tissues in comparison to the
corresponding levels in the normal pancreas (Figure 2)
.
|
|
. ASPC-1, CAPAN-1, MIA-PaCa-2, and
PANC-1 expressed moderate to high levels of Id-1 mRNA, whereas COLO-357
cells expressed relatively low levels of this mRNA moiety. Western
blotting with a highly specific anti-Id-1 antibody confirmed the
presence of the approximately 14-kd Id-1 protein in the 4 cell lines
that expressed high levels of Id-1 mRNA (Figure 3)
. Furthermore, the
three cell lines with the highest Id-1 mRNA expression (CAPAN-1,
MIA-PaCa-2, and PANC-1) also exhibited the highest Id-1 protein
expression. Variable levels of the 1.6-kb Id-2 mRNA transcript were
present in all 5 cell lines. In addition, a minor band of approximately
1.2 kb was visible in COLO-357 and MIA-PaCa-2 cells. Immunoblot
analysis with a highly specific anti-Id-2 antibody revealed two bands
of approximately 16 and 18 kd at relatively high levels in all of the
cell lines with exception of PANC-1 cells, in which the 16-kd band was
relatively faint (Figure 3)
. With the exception of MIA-PaCa-2 cells,
there was a good correlation between Id-2 mRNA and protein levels
(Figure 3)
. Id-3 mRNA was present at high levels in MIA-PaCa-2 cells,
at moderate levels in COLO-357 cells, and at low levels in PANC-1
cells. Id-3 mRNA was not detectable in ASPC-1 and CAPAN-1 cells (Figure 3)
. Immunoblot analysis with a highly specific anti-Id-3 antibody
revealed an approximately 14-kd band that was most abundant in
MIA-PaCa-2 cells, and was also readily apparent in COLO-357 and PANC-1
cells. In contrast, only a faint Id-3 band was seen in ASPC-1 and
CAPAN-1 cells. Thus, with the exception of PANC-1 cells, there was a
good correlation between Id-3 mRNA and protein levels.
|
, and of strong
immunoreactivity in Figure 4C
(left panel). In contrast, in the normal
pancreas, faint Id-1 immunoreactivity was present only in the ductal
cells of pancreatic ducts (Figure 4B
, arrowheads). Preabsorption with
the Id-1-specific blocking peptide completely abolished the Id-1
immunoreactivity (Figure 4C
, right panel). The cancer cells also
exhibited strong Id-2 (Figure 4, D and F
, left panel) and moderate to
strong Id-3 immunoreactivity. An example of moderate Id-3
immunoreactivity is shown in Figure 4G
, and of strong immunoreactivity
in Figure 4I
(left panel). In contrast, only faint Id-2
immunoreactivity was present in the ductal cells in the normal pancreas
(Figure 4E)
, whereas Id-3 immunoreactivity in these cells was more
variable and ranged from moderate to occasionally strong (Figure 4H)
.
Islet cells and acinar cells were always devoid of Id
immunoreactivity. Preabsorption of the respective antibody with the
blocking peptides specific for Id-2 (Figure 4F
, right panel) and Id-3
(Figure 4I
, right panel) completely abolished immunoreactivity.
Analysis of serial pancreatic cancer sections revealed that there was
often colocalization of the three Id proteins. An example of serial
sections from a pancreatic cancer tissue is shown in Figure 4, A, D, and G
.
|
. As
in the normal pancreas, islet cells (outlined by arrowheads) did not
exhibit Id immunoreactivity. In 4 of 9 CP samples, there were foci of
ductal cell dysplasia of relatively large interlobular ducts, all of
which exhibited moderate to strong Id-1, Id-2, and Id-3
immunoreactivity (Figure 5, D–F)
. Five of 9 CP samples also contained
foci of large ducts exhibiting atypical papillary epithelium. Serial
section analysis of one of those CP samples revealed mild to moderate
Id-1 and Id-2 immunoreactivity and weak Id-3 immunoreactivity in the
cells of these atypical papillary ducts (Figure 6, A–C)
. In contrast, in some of these CP
samples, moderate to strong Id-3 immunoreactivity was also observed
(Figure 6D)
. However, most of the ductal cells forming the typical
ductular structures of CP, such as large interlobular ducts and small
proliferating ducts, exhibited generally only weak to occasionally
moderate Id immunoreactivity (data not shown).
|
|
. In the case of Id-1 and Id-2,
the cancer cells as well as the dysplastic and atypical papillary ducts
in CP exhibited a significantly higher score than the ductal cells in
the normal pancreas. In contrast, due to the marked variability in Id-3
immunostaining in the normal pancreas, the differences between normal
and cancer cells and normal and dysplastic cells did not achieve
statistical significance.
|
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
In the present study, we determined by Northern blot analysis that a significant percentage of human pancreatic cancers expressed increased Id-1, Id-2, and Id-3 mRNA levels. Increased expression was most evident for Id-1 (6.5-fold) and Id-2 (fivefold). In contrast, Id-3 mRNA levels were only twofold increased in the cancer samples, partly because this mRNA was present at relatively high levels in the normal pancreas. Immunhistochemical analysis confirmed the presence of Id-1, Id-2, and Id-3 in the cancer cells within the tumor mass, whereas in the normal pancreas faint Id-1 and Id-2 immunoreactivity and moderate to occasionally strong Id-3 immunoreactivity was present in some ductal cells. Pancreatic acinar and islet cells in the normal pancreas were devoid of Id-1, Id-2, and Id-3 immunoreactivity. In the cancer samples, all three Id proteins often colocalized in the cancer cells. Coexpression of all three Id genes was also observed in cultured pancreatic cancer cell lines, which often exhibited a close correlation between Id mRNA and protein expression. However, in MIA-PaCa-2 there was a divergence of Id-2 mRNA and protein levels, and in PANC-1 cells, Id-3 mRNA levels did not correlate well with Id-3 protein expression. These observations suggest that in these cells, the half-life of either Id mRNA or Id protein may be altered by comparison with the other cell lines. Interestingly, Id-2 immunoblotting revealed two closely spaced bands of approximately 16 and 18 kd in 4 of 5 cell lines. In view of the fact that two possible initiation codons have been reported for the Id-2 gene,36 our observation raises the possibility that the two Id-2-immunoreactive bands may represent separate translation products of the Id-2 gene.
Pancreatic cancers often harbor p53 tumor suppressor gene mutations37 and exhibit alterations in apoptosis pathways. Thus, these cancers often exhibit increased expression of anti-apoptotic proteins such as Bcl-238 and abnormal resistance to Fas-ligand-mediated apoptosis.39 It has been shown recently that forced constitutive expression of Id genes together with the expression of anti-apoptotic genes such as Bcl-2 or BclXL can result in malignant transformation of human fibroblasts,11 raising the possibility that the enhanced Id expression in pancreatic cancers together with increased expression of anti-apoptotic genes may contribute to the malignant potential of pancreatic cancer cells in vivo.
In the CP tissues there was no significant increase in Id-1, Id-2, and
Id-3 mRNA levels in comparison to the normal pancreas.
Immunohistochemical analysis of pancreatic cancer samples revealed
colocalization of weak to moderate Id-1, Id-2, and Id-3
immunoreactivity in proliferating ductal cells in the CP-like regions
adjacent to the cancer cells, indicating that Id expression was not
restricted to the cancer cells. Similarly, analysis of CP samples
indicated weak Id-1, Id-2, and Id-3 immunoreactivity in the cells of
small proliferating ducts and large ducts without dysplastic changes.
In general, there was a correlation between weak immunoreactivity and
low Id mRNA levels. However, in samples that harbored large ducts with
papillary structures there was moderate Id immunoreactivity, and in the
cells forming dysplastic ducts there was moderate to strong Id
immunoreactivity. In these CP samples, Id mRNA levels were relatively
higher than in the CP samples that were devoid of these histological
changes. Overall, however, increased Id expression, most notably of
Id-1 and Id-2, distinguished a subgroup of pancreatic cancers from CP
(Table 1)
.
Epidemiological studies have shown that the risk of developing pancreatic cancer is increased up to 16-fold in patients with pre-existing CP in comparison to the general population.40 The mechanisms that contribute to neoplastic transformation in CP are not known. Although there is no established tumor progression model for pancreatic cancer, such as the adenoma-carcinoma sequence of colorectal carcinoma,41 it is generally accepted that K-ras and p16 mutations occur relatively early in pancreatic carcinogenesis, whereas p53 mutations occur late in this process.37,41-43 Increased Id expression may contribute to malignant transformation of cultured cell lines in vitro11 and has been linked to cell invasion in a murine mammary epithelial cell line.44 In view of the current findings that Id-1, Id-2, and Id-3 are overexpressed in pancreatic cancer and in dysplastic/metaplastic ducts in CP, these observations raise the possibility that elevated levels of Id-1, Id-2, and, to a lesser extent, Id-3 may represent relatively early markers of pancreatic malignant transformation and may contribute to the pathobiology of pancreatic cancer.
|
Footnotes |
|---|
Contract grant sponsor: National Cancer Institute. Contract grant number: U. S. Public Health Service grant CA-40162.
Accepted for publication May 24, 1999.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
. J Clin Invest 1992, 90:1352-1360
This article has been cited by other articles:
 |
|
 |
|
  L. Kamalian, J. R. Gosney, S. S. Forootan, C. S. Foster, Z. Z. Bao, C. Beesley, and Y. Ke Increased Expression of Id Family Proteins in Small Cell Lung Cancer and its Prognostic Significance Clin. Cancer Res., April 15, 2008; 14(8): 2318 - 2325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Tsunedomi, N. Iizuka, T. Tamesa, K. Sakamoto, T. Hamaguchi, H. Somura, M. Yamada, and M. Oka Decreased ID2 Promotes Metastatic Potentials of Hepatocellular Carcinoma by Altering Secretion of Vascular Endothelial Growth Factor Clin. Cancer Res., February 15, 2008; 14(4): 1025 - 1031. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. J. Russell, T. Akasaka, A. Majid, K.-j. Sugimoto, E. Loraine Karran, I. Nagel, L. Harder, A. Claviez, S. Gesk, A. V. Moorman, et al. t(6;14)(p22;q32): a new recurrent IGH@ translocation involving ID4 in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) Blood, January 1, 2008; 111(1): 387 - 391. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zhang, M.-T. Ling, Q. Wang, C.-K. Lau, S. C. L. Leung, T. K. Lee, A. L. M. Cheung, Y.-C. Wong, and X. Wang Identification of a Novel Inhibitor of Differentiation-1 (ID-1) Binding Partner, Caveolin-1, and Its Role in Epithelial-Mesenchymal Transition and Resistance to Apoptosis in Prostate Cancer Cells J. Biol. Chem., November 16, 2007; 282(46): 33284 - 33294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Segara, A. V. Biankin, J. G. Kench, C. C. Langusch, A. C. Dawson, D. A. Skalicky, D. C. Gotley, M. J. Coleman, R. L. Sutherland, and S. M. Henshall Expression of HOXB2, a Retinoic Acid Signaling Target in Pancreatic Cancer and Pancreatic Intraepithelial Neoplasia Clin. Cancer Res., May 1, 2005; 11(9): 3587 - 3596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Chaudhary, I. Sadler-Riggleman, J. M. Ague, and M. K. Skinner The Helix-Loop-Helix Inhibitor of Differentiation (ID) Proteins Induce Post-Mitotic Terminally Differentiated Sertoli Cells to Re-Enter the Cell Cycle and Proliferate Biol Reprod, May 1, 2005; 72(5): 1205 - 1217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Kebebew, M. Peng, P. A. Treseler, O. H. Clark, Q.-Y. Duh, D. Ginzinger, and R. Miner Id1 Gene Expression Is Up-Regulated in Hyperplastic and Neoplastic Thyroid Tissue and Regulates Growth and Differentiation in Thyroid Cancer Cells J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6105 - 6111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Lofstedt, A. Jogi, M. Sigvardsson, K. Gradin, L. Poellinger, S. Pahlman, and H. Axelson Induction of ID2 Expression by Hypoxia-inducible Factor-1: A ROLE IN DEDIFFERENTIATION OF HYPOXIC NEUROBLASTOMA CELLS J. Biol. Chem., September 17, 2004; 279(38): 39223 - 39231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. W. Cheung, M.-t. Ling, S. W. Tsao, Y.C. Wong, and X. Wang Id-1-induced Raf/MEK pathway activation is essential for its protective role against taxol-induced apoptosis in nasopharyngeal carcinoma cells Carcinogenesis, June 1, 2004; 25(6): 881 - 887. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-P. Coppe, Y. Itahana, D. H. Moore, J. L. Bennington, and P.-Y. Desprez Id-1 and Id-2 Proteins as Molecular Markers for Human Prostate Cancer Progression Clin. Cancer Res., March 15, 2004; 10(6): 2044 - 2051. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Shan, M. Yu, C. Qiu, and E. G. Snyderwine Id4 Regulates Mammary Epithelial Cell Growth and Differentiation and Is Overexpressed in Rat Mammary Gland Carcinomas Am. J. Pathol., December 1, 2003; 163(6): 2495 - 2502. [Abstract] [Full Text]
|
|
|
|
 |
|
 S. Fong, Y. Itahana, T. Sumida, J. Singh, J.-P. Coppe, Y. Liu, P. C. Richards, J. L. Bennington, N. M. Lee, R. J. Debs, et al. Id-1 as a molecular target in therapy for breast cancer cell invasion and metastasis PNAS, November 11, 2003; 100(23): 13543 - 13548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Tang, G. M. Gordon, M. G. Muller, M. Dahiya, and K. E. Foreman Kaposi's Sarcoma-Associated Herpesvirus Latency-Associated Nuclear Antigen Induces Expression of the Helix-Loop-Helix Protein Id-1 in Human Endothelial Cells J. Virol., May 15, 2003; 77(10): 5975 - 5984. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Schindl, S. F. Schoppmann, T. Strobel, H. Heinzl, C. Leisser, R. Horvat, and P. Birner Level of Id-1 Protein Expression Correlates with Poor Differentiation, Enhanced Malignant Potential, and More Aggressive Clinical Behavior of Epithelial Ovarian Tumors Clin. Cancer Res., February 1, 2003; 9(2): 779 - 785. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. S. Ouyang, X. Wang, M.-T. Ling, H. L. Wong, S. W. Tsao, and Y.C. Wong Id-1 stimulates serum independent prostate cancer cell proliferation through inactivation of p16INK4a/pRB pathway Carcinogenesis, May 1, 2002; 23(5): 721 - 725. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Wilson, R. W. Deed, T. Inoue, M. Balzi, A. Becciolini, P. Faraoni, C. S. Potten, and J. D. Norton Expression of Id Helix-Loop-Helix Proteins in Colorectal Adenocarcinoma Correlates with p53 Expression and Mitotic Index Cancer Res., December 1, 2001; 61(24): 8803 - 8810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. V. Biankin, J. G. Kench, A. L. Morey, C.-S. Lee, S. A. Biankin, D. R. Head, T. B. Hugh, S. M. Henshall, and R. L. Sutherland Overexpression of p21WAF1/CIP1 is an Early Event in the Development of Pancreatic Intraepithelial Neoplasia Cancer Res., December 1, 2001; 61(24): 8830 - 8837. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Schindl, G. Oberhuber, A. Obermair, S. F. Schoppmann, B. Karner, and P. Birner Overexpression of Id-1 Protein Is a Marker for Unfavorable Prognosis in Early-Stage Cervical Cancer Cancer Res., August 1, 2001; 61(15): 5703 - 5706. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Polsky, A. Z. Young, K. J. Busam, and R. M. Alani The Transcriptional Repressor of p16/Ink4a, Id1, Is Up-Regulated in Early Melanomas Cancer Res., August 1, 2001; 61(16): 6008 - 6011. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Alani, A. Z. Young, and C. B. Shifflett Id1 regulation of cellular senescence through transcriptional repression of p16/Ink4a PNAS, June 20, 2001; (2001) 141235398. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Johansen, A. Iwama, T. A. Lodie, K. Sasaki, D. W. Felsher, T. R. Golub, and D. G. Tenen c-Myc Is a Critical Target for C/EBP{alpha} in Granulopoiesis Mol. Cell. Biol., June 1, 2001; 21(11): 3789 - 3806. [Abstract] [Full Text]
|
|
|
|
|
|
X.S. Ouyang, X. Wang, D.T.W. Lee, S.W. Tsao, and Y.C. Wong Up-regulation of TRPM-2, MMP-7 and ID-1 during sex hormone-induced prostate carcinogenesis in the Noble rat Carcinogenesis, June 1, 2001; 22(6): 965 - 973. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Q. Lin, J. Singh, K. Murata, Y. Itahana, S. Parrinello, S. H. Liang, C. E. Gillett, J. Campisi, and P.-Y. Desprez A Role for Id-1 in the Aggressive Phenotype and Steroid Hormone Response of Human Breast Cancer Cells Cancer Res., March 1, 2000; 60(5): 1332 - 1340. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. Norton ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis J. Cell Sci., January 11, 2000; 113(22): 3897 - 3905. [Abstract] [PDF]
|
|
|
|
|
|
|
