| Identity |
| Other names | Wip1 phosphatase |
| PP2C delta (PP2Cd) | |
| EC 3.1.3.16 | |
| HGNC (Hugo) | PPM1D |
| Location | 17q23 |
| Location_base_pair | Starts at 58677554 and ends at 58742036 bp from pter ( according to hg19-Feb_2009) [Mapping] |
| Local_order | centromere - USP32- APPBP2 PPM1D BCAS3 - telomere. |
| DNA/RNA |
| Description | The gene encompasses 64.5 kb of DNA; 6 exons; several SNPs have been found. |
| Transcription | Transcript length: 3,163 bps. Several splice forms have been predicted. Wip1 mRNA transcription is induced in a p53-dependent manner after stress, however p53-independent induction of Wip1 mRNA also has been described. For example, E2F1 was shown to regulate Wip1 expression as well. |
| Protein |
| Note | Other names: Protein phosphatase 2C isoform delta (EC 3.1.3.16) (PP2C-delta) (p53- induced protein phosphatase 1) (Protein phosphatase magnesium- dependent 1 delta). |
| Description | 605 amino acids; predicted size almost 65 kDa, however overexpressed Wip1 runs at almost 83 kDa. |
| Expression | Widely expressed (human expression). |
| Localisation | Primarily nucleus. |
| Function | Wip1 phosphatase is a weak oncogene that can compliment other oncogenes (Hras, Neu:) in transformation of primary rodent cells with low efficiency. Does not complement p53-deficient cells. Wip1 phophatase has broad substrate specificity towards the threonine (p38 and UNG) or the serine residues (ATM, Chk2, p53, H2AX). Deficiency of Wip1 results in activation of p38- and ATM / Chk2-dependent signaling pathways. Inactivation of Wip1 suppresses the ability of mouse embryo fibroblasts undergo transformation in vitro and grow into tumors when explanted into nude mice. Wip1-deficient mice are resistant to multiple types of cancer including breast cancer and B-cell lymphomas. |
| Homology | Other PP2C phospatases |
| Mutations |
| Note | Have not been described. |
| Implicated in |
| Entity | Primary breast cancer |
| Disease | Wip1 overexpression primarily due to its gene amplification was found in almost 15% of primary breast cancers. Majority of Wip1-overexpressing tumors also have structurally intact p53. Overexpression of Wip1 inversely correlates with the level of active (phospho-) p38 MAPK. Wip1-overexpressing tumors also exhibited no or low levels of p16, which normally accumulates upon p38 MAPK activation. PPM1D amplification is associated with ERBB2 expression implying that PPM1D overexpression occurs in tumors with poor prognosis. |
| Prognosis | High expression correlates with poor prognosis. |
| Entity | Neuroblastoma |
| Prognosis | High expression correlates with poor clinical outcome. |
| Entity | Pancreatic adenocarcinoma |
| Prognosis | High expression correlates with poor prognosis. |
| Entity | Ovarian adenocarcinomas |
| Prognosis | High expression correlates with poor prognosis. |
| External links |
| Bibliography |
| Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. |
| Fiscella M, Zhang H, Fan S, Sakaguchi K, Shen S, Mercer WE, Vande Woude GF, O'Connor PM, Appella E |
| Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (12) : 6048-6053. |
| PMID 9177166 |
| p53-inducible wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation. |
| Takekawa M, Adachi M, Nakahata A, Nakayama I, Itoh F, Tsukuda H, Taya Y, Imai K |
| The EMBO journal. 2000 ; 19 (23) : 6517-6526. |
| PMID 11101524 |
| Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. |
| Bulavin DV, Demidov ON, Saito S, Kauraniemi P, Phillips C, Amundson SA, Ambrosino C, Sauter G, Nebreda AR, Anderson CW, Kallioniemi A, Fornace AJ Jr, Appella E |
| Nature genetics. 2002 ; 31 (2) : 210-215. |
| PMID 12021785 |
| Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23. |
| Li J, Yang Y, Peng Y, Austin RJ, van Eyndhoven WG, Nguyen KC, Gabriele T, McCurrach ME, Marks JR, Hoey T, Lowe SW, Powers S |
| Nature genetics. 2002 ; 31 (2) : 133-134. |
| PMID 12021784 |
| Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. |
| Bulavin DV, Phillips C, Nannenga B, Timofeev O, Donehower LA, Anderson CW, Appella E, Fornace AJ Jr |
| Nature genetics. 2004 ; 36 (4) : 343-350. |
| PMID 14991053 |
| The p53-induced oncogenic phosphatase PPM1D interacts with uracil DNA glycosylase and suppresses base excision repair. |
| Lu X, Bocangel D, Nannenga B, Yamaguchi H, Appella E, Donehower LA |
| Molecular cell. 2004 ; 15 (4) : 621-634. |
| PMID 15327777 |
| PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. |
| Lu X, Nannenga B, Donehower LA |
| Genes & development. 2005 ; 19 (10) : 1162-1174. |
| PMID 15870257 |
| Substrate specificity of the human protein phosphatase 2Cdelta, Wip1. |
| Yamaguchi H, Minopoli G, Demidov ON, Chatterjee DK, Anderson CW, Durell SR, Appella E |
| Biochemistry. 2005 ; 44 (14) : 5285-5294. |
| PMID 15807522 |
| Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase. |
| Fujimoto H, Onishi N, Kato N, Takekawa M, Xu XZ, Kosugi A, Kondo T, Imamura M, Oishi I, Yoda A, Minami Y |
| Cell death and differentiation. 2006 ; 13 (7) : 1170-1180. |
| PMID 16311512 |
| Wip1 phosphatase modulates ATM-dependent signaling pathways. |
| Shreeram S, Demidov ON, Hee WK, Yamaguchi H, Onishi N, Kek C, Timofeev ON, Dudgeon C, Fornace AJ, Anderson CW, Minami Y, Appella E, Bulavin DV |
| Molecular cell. 2006 ; 23 (5) : 757-764. |
| PMID 16949371 |
| Regulation of ATM/p53-dependent suppression of myc-induced lymphomas by Wip1 phosphatase. |
| Shreeram S, Hee WK, Demidov ON, Kek C, Yamaguchi H, Fornace AJ Jr, Anderson CW, Appella E, Bulavin DV |
| The Journal of experimental medicine. 2006 ; 203 (13) : 2793-2799. |
| PMID 17158963 |
| Overexpression of the wip1 gene abrogates the p38 MAPK/p53/Wip1 pathway and silences p16 expression in human breast cancers. |
| Yu E, Ahn YS, Jang SJ, Kim MJ, Yoon HS, Gong G, Choi J |
| Breast cancer research and treatment. 2007 ; 101 (3) : 269-278. |
| PMID 16897432 |
| REVIEW articles | automatic search in PubMed |
| Last year publications | automatic search in PubMed |
| Contributor(s) |
| Written | 04-2007 | Dmitry Bulavin, Oleg Demidov |
| 61 Biopolis Dr, Proteos, IMCB, Room 5-13, Singapore, 138673 |
| Citation |
| This paper should be referenced as such : |
| Bulavin D, Demidov O . PPM1D (protein phosphatase 1D magnesium-dependent, delta isoform). Atlas Genet Cytogenet Oncol Haematol. April 2007 . URL : http://AtlasGeneticsOncology.org/Genes/PPM1DID41803ch17q23.html |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Thu Jul 15 14:44:05 CEST 2010 |
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