PPM1D (protein phosphatase 1D magnesium-dependent, delta isoform)

2007-04-01   Dmitry Bulavin , Oleg Demidov 

61 Biopolis Dr, Proteos, IMCB, Room 5-13, Singapore, 138673

Identity

HGNC
LOCATION
17q23.2
LOCUSID
ALIAS
IDDGIP,JDVS,PP2C-DELTA,WIP1
FUSION GENES

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.

Proteins

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 name
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 name
Neuroblastoma
Prognosis
High expression correlates with poor clinical outcome.
Entity name
Pancreatic adenocarcinoma
Prognosis
High expression correlates with poor prognosis.
Entity name
Ovarian adenocarcinomas
Prognosis
High expression correlates with poor prognosis.

Bibliography

Pubmed IDLast YearTitleAuthors
149910532004Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway.Bulavin DV et al
91771661997Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner.Fiscella M et al
163115122006Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase.Fujimoto H et al
120217842002Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23.Li J et al
153277772004The p53-induced oncogenic phosphatase PPM1D interacts with uracil DNA glycosylase and suppresses base excision repair.Lu X et al
158702572005PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints.Lu X et al
171589632006Regulation of ATM/p53-dependent suppression of myc-induced lymphomas by Wip1 phosphatase.Shreeram S et al
111015242000p53-inducible wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation.Takekawa M et al
158075222005Substrate specificity of the human protein phosphatase 2Cdelta, Wip1.Yamaguchi H et al
168974322007Overexpression of the wip1 gene abrogates the p38 MAPK/p53/Wip1 pathway and silences p16 expression in human breast cancers.Yu E et al

Other Information

Locus ID:

NCBI: 8493
MIM: 605100
HGNC: 9277
Ensembl: ENSG00000170836

Variants:

dbSNP: 8493
ClinVar: 8493
TCGA: ENSG00000170836
COSMIC: PPM1D

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000170836ENST00000305921O15297
ENSG00000170836ENST00000305921A0A0S2Z4M2
ENSG00000170836ENST00000392995O15297
ENSG00000170836ENST00000590418K7EJH1
ENSG00000170836ENST00000629650O15297

Expression (GTEx)

0
5
10
15
20
25

Pathways

PathwaySourceExternal ID
p53 signaling pathwayKEGGko04115
p53 signaling pathwayKEGGhsa04115

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
120217852002Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity.150
158702572005PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints.146
169493712006Wip1 phosphatase modulates ATM-dependent signaling pathways.118
179365592007The Wip1 Phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop.114
232421392013Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer.102
120217842002Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23.84
163115122006Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase.70
163146452005Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma.67
201012202010Wip1 phosphatase is associated with chromatin and dephosphorylates gammaH2AX to promote checkpoint inhibition.65
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62

Citation

Dmitry Bulavin ; Oleg Demidov

PPM1D (protein phosphatase 1D magnesium-dependent, delta isoform)

Atlas Genet Cytogenet Oncol Haematol. 2007-04-01

Online version: http://atlasgeneticsoncology.org/gene/41803/ppm1d