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Protein phosphatase 5 and the tumor suppressor p53 down-regulate each other's activities in mice
Jun Wang1, Tao Shen2, Wuqiang Zhu3
1From the Comparative Medical Center, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Beijing 100021, China,; School of Life Sciences, Anhui Agricultural University, Hefei, Anhui 230036, China.
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.
Insights
Protein phosphatase 5 (PP5) directly dephosphorylates and inhibits tumor suppressor p53, impacting genotoxic stress response. Loss of PP5 reduces tumorigenesis, revealing a reciprocal regulatory feedback loop crucial for cellular stress adaptation.
Area of Science:
- Molecular Biology
- Cellular Biology
- Cancer Research
Background:
- Protein phosphatase 5 (PP5) is a serine/threonine phosphatase with diverse biological roles and elevated expression in tumors.
- Previous studies indicated altered ataxia-telangiectasia mutated (ATM)-mediated signaling in pp5-deficient mice, suggesting an indirect regulatory role.
Purpose of the Study:
- To investigate the direct role of PP5 in regulating tumor protein p53 (p53) stability and function.
- To elucidate the reciprocal regulatory relationship between PP5 and p53 in cellular response to genotoxic stress.
Main Methods:
- Utilized pp5-deficient mice and p53 heterozygous/pp5 heterozygous or knockout mice models.
- Performed biochemical analyses including protein interaction and dephosphorylation assays.
- Assessed p53 transcriptional activity and PP5 promoter activity.
Main Results:
- Pp5-deficient mice exhibited hypersensitivity to genotoxic stress, linked to upregulated p53 and its targets (p21, MDM2, PTEN).
- Complete PP5 loss reduced tumorigenesis in p53-haploinsufficient mice.
- PP5 directly dephosphorylates p53, inhibiting its transcriptional activity.
- p53 represses PP5 transcription, indicating a negative feedback loop.
Conclusions:
- PP5 directly regulates p53 stability and function by dephosphorylation.
- A reciprocal regulatory interplay exists between PP5 and p53, forming a feedback mechanism for genotoxic stress response.
- This interaction is critical for cellular adaptation and has implications for cancer development.