Wang, JunShen, TaoZhu, WuqiangDou, LongyuGu, HaoZhang, LinglingYang, ZhenyunChen, HanyingZhou, QiSánchez, Edwin R.Field, Loren J.Mayo, Lindsey D.Xie, ZhongwenXiao, DeyongLin, XiaShou, WeinianYong, Weidong2020-01-062020-01-062018-11-23Wang, J., Shen, T., Zhu, W., Dou, L., Gu, H., Zhang, L., … Yong, W. (2018). Protein phosphatase 5 and the tumor suppressor p53 down-regulate each other's activities in mice. The Journal of biological chemistry, 293(47), 18218–18229. doi:10.1074/jbc.RA118.004256https://hdl.handle.net/1805/21746Protein 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-deficient 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.en-USPublisher PolicyCancerCell stressp53Gene knockoutProtein serine/threonine phosphatase (PSP)Protein phosphorylationProtein phosphatase 5Transcriptional regulationTumorigenesisPosttranslational regulationArticle