Chemotherapy induces NEDP1-mediated destabilization of MDM2.
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.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
I R
IR
Watson
B K
BK
Li
O
O
Roche
A
A
Blanch
M
M
Ohh
M S
MS
Irwin
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D000075687:NEDD8 Protein; D055550:Protein Stability / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism; D009353:Zinostatin / Q000494:pharmacology
D000970:Antineoplastic Agents; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; D004317:Doxorubicin; D009353:Zinostatin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D010450:Endopeptidases; C477008:SENP8 protein, human; D002166:Camptothecin