Chemotherapy Induces NEDP1-Mediated Destabilization of MDM2
Oncogene (2010) 29, 297–304 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 $32.00 www.nature.com/onc SHORT COMMUNICATION Chemotherapy induces NEDP1-mediated destabilization of MDM2 IR Watson1,2,BKLi1,2, O Roche1, A Blanch2, M Ohh1 and MS Irwin1,2,3 1Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; 2Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada and 3Department of Paediatrics and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada MDM2 is an E3 ligase that promotes ubiquitin-mediated In response to DNA damage, p53 becomes phos- destruction of p53. Cellular stresses such as DNA damage phorylated by several kinases within the MDM2- can lead to p53 activation due in part to MDM2 binding domain, which prevents MDM2–p53 interac- destabilization. Here, we show that the stability of tion (Bode and Dong, 2004). The stabilization of p53 MDM2 is regulated by an ubiquitin-like NEDD8 pathway then leads to DNA repair, cell cycle arrest, senescence or and identify NEDP1 as a chemotherapy-induced isopepti- apoptosis. Recent studies have shown that MDM2 is dase that deneddylates MDM2, resulting in MDM2 destabilized in response to DNA damage, which promotes destabilization concomitant with p53 activation. Concor- p53 activation (Stommel and Wahl, 2004; Meulmeester dantly, RNAi-mediated knockdown of endogenous et al., 2005). NEDD8 is a ubiquitin-like protein that NEDP1 blocked diminution of MDM2 levels and regulates protein function through covalent modification increased chemoresistance of tumor cells. These findings of substrates such as Cullins, BCA3, EGFR, ribosomal unveil the regulation of MDM2 stability through NEDP1 L11 protein, VHL, p73 and p53 (Xirodimas, 2008).
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