TY - JOUR
T1 - Protein phosphatase 5 and the tumor suppressor p53 down-regulate each other’s activities in mice
AU - Wang, Jun
AU - Shen, Tao
AU - Zhu, Wuqiang
AU - Dou, Longyu
AU - Gu, Hao
AU - Zhang, Lingling
AU - Yang, Zhenyun
AU - Chen, Hanying
AU - Zhou, Qi
AU - Sánchez, Edwin R.
AU - Field, Loren J.
AU - Mayo, Lindsey D.
AU - Xie, Zhongwen
AU - Xiao, Deyong
AU - Lin, Xia
AU - Shou, Weinian
AU - Yong, Weidong
N1 - Publisher Copyright:
© 2018 Zhang et al.
PY - 2018/11/23
Y1 - 2018/11/23
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.RA118.004256
DO - 10.1074/jbc.RA118.004256
M3 - Article
C2 - 30262665
AN - SCOPUS:85057099687
SN - 0021-9258
VL - 293
SP - 18218
EP - 18229
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 47
ER -