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

Jae Seok Roe, Hwa Ryeon Kim, In Young Hwang, Nam Chul Ha, Seong Tae Kim, Eun Jung Cho, Hong Duk Youn

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20 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3920-3928
Number of pages9
JournalCell Cycle
Volume10
Issue number22
DOIs
Publication statusPublished - 2011 Nov 15

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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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