Materials and Methods
Chemicals and Reagents
Animal and Tissue
Cells and Cell Culture
Western Blot Analysis
Luciferase Activity Assay
RNA Isolation and Quantitative PCR
Cell Death Assay
Histology and Quantitative Thickness Measurement of Retinal Layers
Attenuation of LPS-Induced NF-κB Activation in ARPE-19 Cells by MDM2 Inhibition Is p53 Independent
Attenuation of LPS-Induced NF-κB Activation by Mdm2 Inhibition in the Wild-Type Mice
Attenuation of LPS-Induced NF-κB Activation by Mdm2 Inhibition in p53−/− Mice
Systemic Mdm2 Inhibition Is Effective in Inhibiting LPS-Induced Inflammatory Cell Infiltration in Anterior and Posterior Segments of the Eye
Supratherapeutic Nutlin-3 Does Not Appear to Cause Retinal Cell Death
LPS-Induced Transcription and Translation of NF-κB Are Suppressed by MDM2 Inhibition
- Yang J.Y.
- Zong C.S.
- Xia W.
- Yamaguchi H.
- Ding Q.
- Xie X.
- Lang J.Y.
- Lai C.C.
- Chang C.J.
- Huang W.C.
- Huang H.
- Kuo H.P.
- Lee D.F.
- Li L.Y.
- Lien H.C.
- Cheng X.
- Chang K.J.
- Hsiao C.D.
- Tsai F.J.
- Tsai C.H.
- Sahin A.A.
- Muller W.J.
- Mills G.B.
- Yu D.
- Hortobagyi G.N.
- Hung M.C.
- Supplemental Figure S1
Determination of the time point of lipopolysaccharide (LPS) i.p. injection in wild-type mice. Wild-type mice were intraperitoneally injected with 200 mg LPS; retina and choroid were harvested at indicated time points and used for quantitative PCR analysis of Tnfa (A), Il6 (B), and Ccl2 [monocyte chemotactic protein-1 (MCP-1); C] expression; GAPDH was included as a loading control. Data are expressed as means ± SD of three independent experiments (A–C). ∗P < 0.05, ∗∗∗P < 0.001 compared with control.
- Supplemental Figure S2
There is no inflammatory cell infiltration in vehicle- or Nutlin-3–injected eyes. Adult wild-type mice (A and C) and p53−/− mice (B and D) were intraperitoneally injected with vehicle (A and B) or Nutlin-3 (C and D). Whole eyes were subjected to hematoxylin and eosin staining.
- Incidence and prevalence of uveitis in Northern California: the Northern California Epidemiology of Uveitis Study.Ophthalmology. 2004; 111 (discussion 500): 491-500
- Uveitis: pathogenesis.Lancet. 1991; 338: 1498-1501
- Experimental autoimmune uveitis and its relationship to clinical ocular inflammatory disease.J Autoimmun. 1996; 9: 575-585
- A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy.Allergy Asthma Clin Immunol. 2013; 9: 30
- What causes steroid cataracts? a review of steroid-induced posterior subcapsular cataracts.Clin Exp Optom. 2002; 85: 61-75
- Harefuah. 2003; 142 (Hebrew) (157): 137-140
- Clinical outcome of chronic immunosuppression in patients with non-infectious uveitis.Clin Exp Ophthalmol. 2005; 33: 16-21
- Critical contribution of the MDM2 acidic domain to p53 ubiquitination.Mol Cell Biol. 2003; 23: 4939-4947
- MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer.J Hematol Oncol. 2017; 10: 133
- Clinical overview of MDM2/X-targeted therapies.Front Oncol. 2016; 6: 7
- MDM2 (murine double minute-2) links inflammation and tubular cell healing during acute kidney injury in mice.Kidney Int. 2012; 81: 1199-1211
- MDM2 induces NF-kappaB/p65 expression transcriptionally through Sp1-binding sites: a novel, p53-independent role of MDM2 in doxorubicin resistance in acute lymphoblastic leukemia.Blood. 2002; 99: 3367-3375
- p53-Independent roles of MDM2 in NF-kappaB signaling: implications for cancer therapy, wound healing, and autoimmune diseases.Neoplasia. 2012; 14: 1097-1101
- Retinal angiogenesis suppression through small molecule activation of p53.J Clin Invest. 2013; 123: 4170-4181
- The retinal pigment epithelium in health and disease.Curr Mol Med. 2010; 10: 802-823
- ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation.Nat Cell Biol. 2008; 10: 138-148
- Targeted expression of MDM2 uncouples S phase from mitosis and inhibits mammary gland development independent of p53.Genes Dev. 1997; 11: 714-725
- Mdm2 promotes genetic instability and transformation independent of p53.Mol Cell Biol. 2008; 28: 4862-4874
- In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.Science. 2004; 303: 844-848
- Integrated high-throughput analysis identifies Sp1 as a crucial determinant of p53-mediated apoptosis.Cell Death Differ. 2014; 21: 1493-1502
- Functional interference of Sp1 and NF-kappaB through the same DNA binding site.Mol Cell Biol. 1998; 18: 1266-1274
- Inhibition of Mdm2 sensitizes human retinal pigment epithelial cells to apoptosis.Invest Ophthalmol Vis Sci. 2011; 52: 3368-3380
- Age-related susceptibility to apoptosis in human retinal pigment epithelial cells is triggered by disruption of p53-Mdm2 association.Invest Ophthalmol Vis Sci. 2012; 53: 8350-8366
See related commentary on page 1953
Supported by the Nancy Lee and Perry R. Bass Endowment, the Foundation Fighting Blindness, and National Eye Institute awards EY021171 and EY025667 (S.H.C.).
Disclosures: S.H.C. filed patent application 61/386,808, “MDM2 inhibitors for treatment of ocular conditions,” on September 27, 2010. S.H.C. is a founder of Serrata LLC, a start-up company that plans to commercialize novel treatments for ocular diseases.
User LicenseElsevier user license |
For non-commercial purposes:
- Read, print & download
- Text & data mine
- Translate the article
- Reuse portions or extracts from the article in other works
- Redistribute or republish the final article
- Sell or re-use for commercial purposes
Elsevier's open access license policy