Phosphorylation by Casein Kinase I promotes the turnover of the Mdm2 oncoprotein via the SCFβ-TRCP ubiquitin ligase

Hiroyuki Inuzuka, Alan Tseng, Daming Gao, Bo Zhai, Qing Zhang, Shavali Shaik, Lixin Wan, Xiaolu L. Ang, Caroline Mock, Haoqiang Yin, Jayne M. Stommel, Steven Gygi, Galit Lahav, John Asara, Zhi Xiong Jim Xiao, William G. Kaelin, J. Wade Harper, Wenyi Wei

Research output: Contribution to journalArticle

135 Scopus citations

Abstract

Mdm2 is the major negative regulator of the p53 pathway. Here, we report that Mdm2 is rapidly degraded after DNA damage and that phosphorylation of Mdm2 by casein kinase I (CKI) at multiple sites triggers its interaction with, and subsequent ubiquitination and destruction, by SCFβ-TRCP. Inactivation of either β-TRCP or CKI results in accumulation of Mdm2 and decreased p53 activity, and resistance to apoptosis induced by DNA damaging agents. Moreover, SCFβ-TRCP-dependent Mdm2 turnover also contributes to the control of repeated p53 pulses in response to persistent DNA damage. Our results provide insight into the signaling pathways controlling Mdm2 destruction and further suggest that compromised regulation of Mdm2 results in attenuated p53 activity, thereby facilitating tumor progression.

Original languageEnglish (US)
Pages (from-to)147-159
Number of pages13
JournalCancer Cell
Volume18
Issue number2
DOIs
StatePublished - Aug 1 2010
Externally publishedYes

Keywords

  • Cellcycle

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Inuzuka, H., Tseng, A., Gao, D., Zhai, B., Zhang, Q., Shaik, S., Wan, L., Ang, X. L., Mock, C., Yin, H., Stommel, J. M., Gygi, S., Lahav, G., Asara, J., Xiao, Z. X. J., Kaelin, W. G., Harper, J. W., & Wei, W. (2010). Phosphorylation by Casein Kinase I promotes the turnover of the Mdm2 oncoprotein via the SCFβ-TRCP ubiquitin ligase. Cancer Cell, 18(2), 147-159. https://doi.org/10.1016/j.ccr.2010.06.015