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

Research output: Contribution to journalArticle

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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.

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

Fingerprint

Checkpoint Kinase 2
Protein Kinases
Transcriptional Activation
DNA Damage
Phosphorylation
Carcinogenesis
Kidney
p53 Genes
Chromatin
Transcription Factors
Apoptosis
Growth
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

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
Roe, Jae-Seok ; Kim, Hwa Ryeon ; Hwang, In Young ; Ha, Nam Chul ; Kim, Seong Tae ; Cho, Eun Jung ; Youn, Hong Duk. / Phosphorylation of von Hippel-Lindau protein by checkpoint kinase 2 regulates p53 transactivation. In: Cell Cycle. 2011 ; Vol. 10, No. 22. pp. 3920-3928.
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Roe, J-S, Kim, HR, Hwang, IY, Ha, NC, Kim, ST, Cho, EJ & Youn, HD 2011, 'Phosphorylation of von Hippel-Lindau protein by checkpoint kinase 2 regulates p53 transactivation', Cell Cycle, vol. 10, no. 22, pp. 3920-3928. https://doi.org/10.4161/cc.10.22.18096

Phosphorylation of von Hippel-Lindau protein by checkpoint kinase 2 regulates p53 transactivation. / Roe, Jae-Seok; Kim, Hwa Ryeon; Hwang, In Young; Ha, Nam Chul; Kim, Seong Tae; Cho, Eun Jung; Youn, Hong Duk.

In: Cell Cycle, Vol. 10, No. 22, 15.11.2011, p. 3920-3928.

Research output: Contribution to journalArticle

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