| First Author | Wang J | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 47 | Pages | 18218-18229 |
| PubMed ID | 30262665 | Mgi Jnum | J:272817 |
| Mgi Id | MGI:6268571 | Doi | 10.1074/jbc.RA118.004256 |
| Citation | Wang J, et al. (2018) Protein phosphatase 5 and the tumor suppressor p53 down-regulate each other's activities in mice. J Biol Chem 293(47):18218-18229 |
| abstractText | 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. |
