Abstract B1: 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...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2009-12, Vol.69 (23_Supplement), p.B1-B1
Main Authors: Watson, Ian R., Li, Bryan K., Roche, Olga, Blanch, Alvaro, Ohh, Michael, Irwin, Meredith S.
Format: Article
Language:English
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Summary: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, RNA-imediated knockdown of endogenous NEDP1 blocked diminution of MDM2 levels and increased chemoresistance of tumor cells. These findings unveil the regulation of MDM2 stability via NEDP1 as a common molecular determinant governing chemotherapy-induced p53-dependent cell death. Citation Information: Cancer Res 2009;69(23 Suppl):B1.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.FBCR09-B1