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

Abstract

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.

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Fig. 1: p53 target genes for apoptosis and angiogenesis are altered by VHL status.
Fig. 2: Mdm2 binds to VHL and inhibits VHL–p53 complex formation under hypoxia.
Fig. 3: Neddylation of VHL by Mdm2 interferes with VHL–p53 complex formation.
Fig. 4: VHL forms a complex with p53 under hypoxia or with treatment of MLN4924.
Fig. 5: VHL increases the activation of p53 under hypoxia leading to increased transcription and secretion of TSP-1.
Fig. 6: p53 and TSP-1 inhibit human umbilical vein endothelial cell network formation.

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Acknowledgements

This research was supported by NIH/NCI CA172256 and the Riley Children’s Foundation. We thank Dr. Ohh for the VHL expression plasmid, Dr. Bouck for the Thrombospondin reporter plasmid, and Dr. Ivan for the renal cell carcinoma cell lines to aid in this study.

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Correspondence to Lindsey D. Mayo.

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Wolf, E.R., Mabry, A.R., Damania, B. et al. Mdm2-mediated neddylation of pVHL blocks the induction of antiangiogenic factors. Oncogene 39, 5228–5239 (2020). https://doi.org/10.1038/s41388-020-1359-4

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