Mdm2-mediated neddylation of pVHL blocks the induction of antiangiogenic factors

Eric R. Wolf, Alexander R. Mabry, Blossom Damania, Lindsey D. Mayo

Research output: Contribution to journalArticle


Mutations in the tumor suppressor TP53 are rare in renal cell carcinomas. p53 is a key factor for inducing antiangiogenic genes and RCC are highly vascularized, which suggests that p53 is inactive in these tumors. One regulator of p53 is the Mdm2 oncogene, which is correlated with high-grade, metastatic tumors. However, the sole activity of Mdm2 is not just to regulate p53, but it can also function independent of p53 to regulate the early stages of metastasis. Here, we report that the oncoprotein Mdm2 can bind directly to the tumor suppressor VHL, and conjugate nedd8 to VHL within a region that is important for the p53–VHL interaction. Nedd8 conjugated VHL is unable to bind to p53 thereby preventing the induction of antiangiogenic factors. These results highlight a previously unknown oncogenic function of Mdm2 during the progression of cancer to promote angiogenesis through the regulation of VHL. Thus, the Mdm2–VHL interaction represents a pathway that impacts tumor angiogenesis.

Original languageEnglish (US)
Pages (from-to)5228-5239
Number of pages12
Issue number29
StatePublished - Jul 16 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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