Protein phosphatase 5 and the tumor suppressor p53 down-regulate each other’s activities in mice

Jun Wang, Tao Shen, Wuqiang Zhu, Longyu Dou, Hao Gu, Lingling Zhang, Zhenyun Yang, Hanying Chen, Qi Zhou, Edwin R. Sánchez, Loren J. Field, Lindsey D. Mayo, Zhongwen Xie, Deyong Xiao, Xia Lin, Weinian Shou, Weidong Yong

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Protein phosphatase 5 (PP5), a serine/threonine phosphatase, has a wide range of biological functions and exhibits elevated expression in tumor cells. We previously reported that pp5-de-ficient mice have altered ataxia-telangiectasia mutated (ATM)mediated signaling and function. However, this regulation was likely indirect, as ATM is not a known PP5 substrate. In the current study, we found that pp5-deficient mice are hypersensitive to genotoxic stress. This hypersensitivity was associated with the marked up-regulation of the tumor suppressor tumor protein p53 and its downstream targets cyclin-dependent kinase inhibitor 1A (p21), MDM2 proto-oncogene (MDM2), and phosphatase and tensin homolog (PTEN) in pp5-deficient tissues and cells. These observations suggested that PP5 plays a role in regulating p53 stability and function. Experiments conducted with p53/pp5/ or p53/pp5/ mice revealed that complete loss of PP5 reduces tumorigenesis in the p53/ mice. Biochemical analyses further revealed that PP5 directly interacts with and dephosphorylates p53 at multiple serine/threonine residues, resulting in inhibition of p53-mediated transcriptional activity. Interestingly, PP5 expression was significantly up-regulated in p53-deficient cells, and further analysis of pp5 promoter activity revealed that p53 strongly represses PP5 transcription. Our results suggest a reciprocal regulatory interplay between PP5 and p53, providing an important feedback mechanism for the cellular response to genotoxic stress.

Original languageEnglish (US)
Pages (from-to)18218-18229
Number of pages12
JournalJournal of Biological Chemistry
Volume293
Issue number47
DOIs
StatePublished - Nov 23 2018

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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