PPM1D (protein phosphatase 1D magnesium-dependent, delta isoform)
2007-04-01 Dmitry Bulavin , Oleg Demidov Affiliation61 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.
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.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 14991053 | 2004 | Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. | Bulavin DV et al |
| 9177166 | 1997 | Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner. | Fiscella M et al |
| 16311512 | 2006 | Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase. | Fujimoto H et al |
| 12021784 | 2002 | Oncogenic properties of PPM1D located within a breast cancer amplification epicenter at 17q23. | Li J et al |
| 15327777 | 2004 | The p53-induced oncogenic phosphatase PPM1D interacts with uracil DNA glycosylase and suppresses base excision repair. | Lu X et al |
| 15870257 | 2005 | PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. | Lu X et al |
| 17158963 | 2006 | Regulation of ATM/p53-dependent suppression of myc-induced lymphomas by Wip1 phosphatase. | Shreeram S et al |
| 11101524 | 2000 | p53-inducible wip1 phosphatase mediates a negative feedback regulation of p38 MAPK-p53 signaling in response to UV radiation. | Takekawa M et al |
| 15807522 | 2005 | Substrate specificity of the human protein phosphatase 2Cdelta, Wip1. | Yamaguchi H et al |
| 16897432 | 2007 | Overexpression 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
Expression (GTEx)
Pathways
| Pathway | Source | External ID |
|---|---|---|
| p53 signaling pathway | KEGG | ko04115 |
| p53 signaling pathway | KEGG | hsa04115 |
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37067201 | 2024 | PPM1D activity promotes the replication stress caused by cyclin E1 overexpression. | 0 |
| 38896450 | 2024 | SOD1 is a synthetic-lethal target in PPM1D-mutant leukemia cells. | 1 |
| 37067201 | 2024 | PPM1D activity promotes the replication stress caused by cyclin E1 overexpression. | 0 |
| 38896450 | 2024 | SOD1 is a synthetic-lethal target in PPM1D-mutant leukemia cells. | 1 |
| 37183572 | 2023 | Jansen-de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families. | 4 |
| 37378944 | 2023 | A Case Study on PPM1D and 9 Other Shared Germline Alterations in a Family. | 0 |
| 37595362 | 2023 | PPM1D modulates hematopoietic cell fitness and response to DNA damage and is a therapeutic target in myeloid malignancy. | 3 |
| 38132396 | 2023 | Low-Frequency PPM1D Gene Mutations Affect Treatment Response to CD19-Targeted CAR T-Cell Therapy in Large B-Cell Lymphoma. | 1 |
| 37183572 | 2023 | Jansen-de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families. | 4 |
| 37378944 | 2023 | A Case Study on PPM1D and 9 Other Shared Germline Alterations in a Family. | 0 |
| 37595362 | 2023 | PPM1D modulates hematopoietic cell fitness and response to DNA damage and is a therapeutic target in myeloid malignancy. | 3 |
| 38132396 | 2023 | Low-Frequency PPM1D Gene Mutations Affect Treatment Response to CD19-Targeted CAR T-Cell Therapy in Large B-Cell Lymphoma. | 1 |
| 35025619 | 2022 | Mutant PPM1D- and TP53-Driven Hematopoiesis Populates the Hematopoietic Compartment in Response to Peptide Receptor Radionuclide Therapy. | 13 |
| 35105861 | 2022 | PPM1D mutations are oncogenic drivers of de novo diffuse midline glioma formation. | 19 |
| 35490254 | 2022 | Differential roles of the Wip1-p38-p53 DNA damage response pathway in early/advanced-stage ovarian clear cell carcinomas. | 1 |
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
