Browsing by Subject "Protein serine/threonine phosphatase (PSP)"

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    Protein phosphatase 5 and the tumor suppressor p53 down-regulate each other's activities in mice
    (American Society for Biochemistry and Molecular Biology, 2018-11-23) Wang, Jun; Shen, Tao; Zhu, Wuqiang; Dou, Longyu; Gu, Hao; Zhang, Lingling; Yang, Zhenyun; Chen, Hanying; Zhou, Qi; Sánchez, Edwin R.; Field, Loren J.; Mayo, Lindsey D.; Xie, Zhongwen; Xiao, Deyong; Lin, Xia; Shou, Weinian; Yong, Weidong; Pediatrics, School of Medicine
    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-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.