Chemotherapy induces NEDP1-mediated destabilization of MDM2

• Published in: Oncogene Vol. 29; no. 2; pp. 297 - 304
• Main Authors: Watson, I R, Li, B K, Roche, O, Blanch, A, Ohh, M, Irwin, M S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.01.2010; Nature Publishing Group
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Camptothecin - pharmacology; Cancer; Cell Biology; Cell Line; Cell Line, Tumor; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chemotherapy; DNA damage; Doxorubicin - pharmacology; Endopeptidases - genetics; Endopeptidases - metabolism; Fundamental and applied biological sciences. Psychology; Genetic aspects; Health aspects; HeLa Cells; Human Genetics; Humans; Immunoblotting; Internal Medicine; Ligases; Medicine; Medicine & Public Health; Molecular and cellular biology; NEDD8 Protein; Oncology; Physiological aspects; Protein Stability - drug effects; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; RNA Interference; short-communication; Transfection; Tumor suppressor genes; Tumor Suppressor Protein p53 - metabolism; Ubiquitins - genetics; Ubiquitins - metabolism; Zinostatin - pharmacology; Canada; MDM2; NEDD8; NEDP1; chemotherapy; p53; Chemotherapy; Treatment; TP53 Gene; Carcinogenesis; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2009.314

MDM2 is an E3 ligase that promotes ubiquitin-mediated destruction of p53. Cellular stresses such as DNA damage can lead to p53 activation due in part to MDM2 destabilization. Here, we show that the stability of MDM2 is regulated by an ubiquitin-like NEDD8 pathway and identify NEDP1 as a chemotherapy-induced isopeptidase that deneddylates MDM2, resulting in MDM2 destabilization concomitant with p53 activation. Concordantly, RNAi-mediated knockdown of endogenous NEDP1 blocked diminution of MDM2 levels and increased chemoresistance of tumor cells. These findings unveil the regulation of MDM2 stability through NEDP1 as a common molecular determinant governing chemotherapy-induced p53-dependent cell death.