PPM1D explained

Protein phosphatase 1D is an enzyme that in humans is encoded by the PPM1D gene.^{[1] [2]}

The protein encoded by this gene is a member of the PP2C family of Ser/Thr protein phosphatases. PP2C family members are known to be negative regulators of cell stress response pathways. The expression of this gene is induced in a p53-dependent manner in response to various environmental stresses. While being induced by tumor suppressor protein TP53/p53, this phosphatase negatively regulates the activity of p38 MAP kinase (MAPK/p38) through which it reduces the phosphorylation of p53, and in turn suppresses p53-mediated transcription and apoptosis. This phosphatase thus mediates a feedback regulation of p38-p53 signaling that contributes to growth inhibition and the suppression of stress induced apoptosis. This gene is located in a chromosomal region known to be amplified in breast cancer. The amplification of this gene has been detected in both breast cancer cell line and primary breast tumors, which suggests a role of this gene in cancer development.^[2] Pathogenic variants in exons 5-6 in the PPM1D gene can cause the neurodevelopmental disorder known as Jansen-de Vries Syndrome (JdVS).^[3]

Interactions

PPM1D has been shown to interact with CDC5L.^[4]

Further reading

• Adams MD, Kerlavage AR, Fleischmann RD, etal . Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence. . Nature . 377 . 6547 Suppl . 3–174 . 1995 . 7566098 .
• Hirano K, Ito M, Hartshorne DJ . Interaction of the ribosomal protein, L5, with protein phosphatase type 1. . J. Biol. Chem. . 270 . 34 . 19786–90 . 1995 . 7649987 . 10.1074/jbc.270.34.19786 . free .
• Takekawa M, Adachi M, Nakahata A, etal . p53-inducible wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation. . EMBO J. . 19 . 23 . 6517–26 . 2001 . 11101524 . 10.1093/emboj/19.23.6517 . 305857 .
• Ajuh P, Kuster B, Panov K, etal . Functional analysis of the human CDC5L complex and identification of its components by mass spectrometry. . EMBO J. . 19 . 23 . 6569–81 . 2001 . 11101529 . 10.1093/emboj/19.23.6569 . 305846 .
• Choi J, Nannenga B, Demidov ON, etal . Mice deficient for the wild-type p53-induced phosphatase gene (Wip1) exhibit defects in reproductive organs, immune function, and cell cycle control. . Mol. Cell. Biol. . 22 . 4 . 1094–105 . 2002 . 11809801 . 10.1128/MCB.22.4.1094-1105.2002 . 134641 .
• Li J, Yang Y, Peng Y, etal . Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23. . Nat. Genet. . 31 . 2 . 133–4 . 2002 . 12021784 . 10.1038/ng888 . 5750250 .
• Bulavin DV, Demidov ON, Saito S, etal . Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. . Nat. Genet. . 31 . 2 . 210–5 . 2002 . 12021785 . 10.1038/ng894 . 30048056 .
• Morimoto H, Okamura H, Haneji T . Interaction of protein phosphatase 1 delta with nucleolin in human osteoblastic cells. . J. Histochem. Cytochem. . 50 . 9 . 1187–93 . 2002 . 12185196 . 10.1177/002215540205000905. free .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Imabayashi H, Mori T, Gojo S, etal . Redifferentiation of dedifferentiated chondrocytes and chondrogenesis of human bone marrow stromal cells via chondrosphere formation with expression profiling by large-scale cDNA analysis. . Exp. Cell Res. . 288 . 1 . 35–50 . 2003 . 12878157 . 10.1016/S0014-4827(03)00130-7 .
• Bernards R . Wip-ing out cancer. . Nat. Genet. . 36 . 4 . 319–20 . 2004 . 15054481 . 10.1038/ng0404-319 . free .
• Lu X, Bocangel D, Nannenga B, etal . The p53-induced oncogenic phosphatase PPM1D interacts with uracil DNA glycosylase and suppresses base excision repair. . Mol. Cell . 15 . 4 . 621–34 . 2004 . 15327777 . 10.1016/j.molcel.2004.08.007 . free .
• Gerhard DS, Wagner L, Feingold EA, etal . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• Yamaguchi H, Minopoli G, Demidov ON, etal . Substrate specificity of the human protein phosphatase 2Cdelta, Wip1. . Biochemistry . 44 . 14 . 5285–94 . 2005 . 15807522 . 10.1021/bi0476634 .
• Lu X, Nannenga B, Donehower LA . PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. . Genes Dev. . 19 . 10 . 1162–74 . 2005 . 15870257 . 10.1101/gad.1291305 . 1132003 .
• Rual JF, Venkatesan K, Hao T, etal . Towards a proteome-scale map of the human protein-protein interaction network. . Nature . 437 . 7062 . 1173–8 . 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
• Rauta J, Alarmo EL, Kauraniemi P, etal . The serine-threonine protein phosphatase PPM1D is frequently activated through amplification in aggressive primary breast tumours. . Breast Cancer Res. Treat. . 95 . 3 . 257–63 . 2006 . 16254685 . 10.1007/s10549-005-9017-7 . 9693018 .
• Fujimoto H, Onishi N, Kato N, etal . Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase. . Cell Death Differ. . 13 . 7 . 1170–80 . 2006 . 16311512 . 10.1038/sj.cdd.4401801 . free .
• Mendrzyk F, Radlwimmer B, Joos S, etal . Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma. . J. Clin. Oncol. . 23 . 34 . 8853–62 . 2006 . 16314645 . 10.1200/JCO.2005.02.8589 .

Notes and References

1. Fiscella M, Zhang H, Fan S, Sakaguchi K, Shen S, Mercer WE, Vande Woude GF, O'Connor PM, Appella E . Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner . Proc Natl Acad Sci U S A . 94 . 12 . 6048–53 . July 1997 . 9177166 . 20998 . 10.1073/pnas.94.12.6048 . 1997PNAS...94.6048F . free .
2. Web site: Entrez Gene: PPM1D protein phosphatase 1D magnesium-dependent, delta isoform.
3. Wojcik . Monica H . Srivastava . Siddharth . Agrawal . Pankaj B . Balci . Tugce B . Callewaert . Bert . Calvo . Pier Luigi . Carli . Diana . Caudle . Michelle . Colaiacovo . Samantha . Cross . Laura . Demetriou . Kalliope . Drazba . Katy . Dutra-Clarke . Marina . Edwards . Matthew . Genetti . Casie A . July 2023 . Jansen-DeVries Syndrome: Expansion of the PPM1D Clinical and Phenotypic Spectrum in 34 Families . American Journal of Medical Genetics. Part A . 191 . 7 . 1900–1910 . 10.1002/ajmg.a.63226 . 1552-4825 . 37183572. 10330231 .
4. Ajuh . P . Kuster B . Panov K . Zomerdijk J C . Mann M . Lamond A I . December 2000 . Functional analysis of the human CDC5L complex and identification of its components by mass spectrometry . EMBO J. . 19 . 23 . 6569–81 . 0261-4189. 11101529 . 10.1093/emboj/19.23.6569 . 305846 .