Phosphorylation of von Hippel-Lindau protein by checkpoint kinase 2 regulates p53 transactivation

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Abstract

von-Hippel Lindau protein (pVHL) suppresses tumorigenesis in the kidney, in part through regulation of hypoxiainducible factor α (HIFα). However, HIF has been proposed to be necessary but insufficient for renal tumorigenesis. p53 was implicated as a transcription factor that is regulated by pVHL, but the molecular mechanism by which pVHL regulates p53 on DNA damage is unknown. We demonstrated that checkpoint kinase-2 (Chk2) binds to the β-domain of pVHL and phosphorylates Ser 111 on DNA damage. Notably, this modification enhances pVHL-mediated transactivation of p53 by recruiting p300 and Tip60 to the chromatin of p53 target gene. Further, the naturally occurring pVHL mutants pVHL-S111R and pVHL-S111C showed diminished binding to coactivators, ultimately retarding p53-mediated growth arrest and apoptosis. In this study, we determined the molecular mechanism by which pVHL transactivates p53 on DNA damage and demonstrated that p53-related pVHL subtype mutants regulate tumorigenecity in VHL diseases. © 2011 Landes Bioscience.

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Roe, J. S., Kim, H. R., Hwang, I. Y., Ha, N. C., Kim, S. T., Cho, E. J., & Youn, H. D. (2011). Phosphorylation of von Hippel-Lindau protein by checkpoint kinase 2 regulates p53 transactivation. Cell Cycle, 10(22), 3920–3928. https://doi.org/10.4161/cc.10.22.18096

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