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 Field, Lindsey Mayo, Zhongwen Xie, Deyong Xiao, Xia Lin, Weinian Shou, Weidong Yong

Research output: Contribution to journalArticle

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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-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.

Original languageEnglish (US)
Pages (from-to)18218-18229
Number of pages12
JournalThe Journal of biological chemistry
Volume293
Issue number47
DOIs
StatePublished - Nov 23 2018

Fingerprint

Tumors
Down-Regulation
Neoplasms
Ataxia Telangiectasia
DNA Damage
Cyclin-Dependent Kinase Inhibitor p21
Tumor Suppressor Protein p53
Proto-Oncogenes
Cyclin-Dependent Kinases
protein phosphatase 5
Phosphoprotein Phosphatases
Threonine
Transcription
Phosphoric Monoester Hydrolases
Serine
Hypersensitivity
Carcinogenesis
Up-Regulation
Cells
Tissue

Keywords

  • cancer
  • cell stress
  • gene knockout
  • p53
  • posttranslational regulation
  • protein phosphatase 5
  • protein phosphorylation
  • protein serine/threonine phosphatase (PSP)
  • transcriptional regulation
  • tumorigenesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Protein phosphatase 5 and the tumor suppressor p53 down-regulate each other's activities in mice. / Wang, Jun; Shen, Tao; Zhu, Wuqiang; Dou, Longyu; Gu, Hao; Zhang, Lingling; Yang, Zhenyun; Chen, Hanying; Zhou, Qi; Sánchez, Edwin R.; Field, Loren; Mayo, Lindsey; Xie, Zhongwen; Xiao, Deyong; Lin, Xia; Shou, Weinian; Yong, Weidong.

In: The Journal of biological chemistry, Vol. 293, No. 47, 23.11.2018, p. 18218-18229.

Research output: Contribution to journalArticle

Wang, J, Shen, T, Zhu, W, Dou, L, Gu, H, Zhang, L, Yang, Z, Chen, H, Zhou, Q, Sánchez, ER, Field, L, Mayo, L, Xie, Z, Xiao, D, Lin, X, Shou, W & Yong, W 2018, 'Protein phosphatase 5 and the tumor suppressor p53 down-regulate each other's activities in mice', The Journal of biological chemistry, vol. 293, no. 47, pp. 18218-18229. https://doi.org/10.1074/jbc.RA118.004256
Wang, Jun ; Shen, Tao ; Zhu, Wuqiang ; Dou, Longyu ; Gu, Hao ; Zhang, Lingling ; Yang, Zhenyun ; Chen, Hanying ; Zhou, Qi ; Sánchez, Edwin R. ; Field, Loren ; Mayo, Lindsey ; Xie, Zhongwen ; Xiao, Deyong ; Lin, Xia ; Shou, Weinian ; Yong, Weidong. / Protein phosphatase 5 and the tumor suppressor p53 down-regulate each other's activities in mice. In: The Journal of biological chemistry. 2018 ; Vol. 293, No. 47. pp. 18218-18229.
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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-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.",
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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

AU - Mayo, Lindsey

AU - Xie, Zhongwen

AU - Xiao, Deyong

AU - Lin, Xia

AU - Shou, Weinian

AU - Yong, Weidong

PY - 2018/11/23

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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-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.

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-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.

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KW - protein serine/threonine phosphatase (PSP)

KW - transcriptional regulation

KW - tumorigenesis

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