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

Written2007-04Dmitry Bulavin, Oleg Demidov
61 Biopolis Dr, Proteos, IMCB, Room 5-13, Singapore, 138673

(Note : for Links provided by Atlas : click)

Identity

Alias_namesprotein phosphatase 1D magnesium-dependent, delta isoform
protein phosphatase, Mg2?? dependent, 1D
Alias_symbol (synonym)Wip1
PP2C-DELTA
HGNC (Hugo) PPM1D
LocusID (NCBI) 8493
Atlas_Id 41803
Location 17q23.2  [Link to chromosome band 17q23]
Location_base_pair Starts at 58677544 and ends at 58743640 bp from pter ( according to hg19-Feb_2009)  [Mapping PPM1D.png]
Local_order centromere - USP32- APPBP2   PPM1D   BCAS3 - telomere.
Fusion genes
(updated 2016)
PGAP3 (17q12) / PPM1D (17q23.2)PPM1D (17q23.2) / C17orf64 (17q23.2)PPM1D (17q23.2) / NUP85 (17q25.1)
PPM1D (17q23.2) / RAD54B (8q22.1)PPM1D (17q23.2) / TRAPPC9 (8q24.3)PPM1D (17q23.2) / TRIM37 (17q22)
STXBP4 (17q22) / PPM1D (17q23.2)

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

Note
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.
  

Bibliography

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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 

Citation

This paper should be referenced as such :
Bulavin, Dmitry ; Demidov, Oleg
PPM1D (protein phosphatase 1D magnesium-dependent, delta isoform)
Atlas Genet Cytogenet Oncol Haematol. 2007;11(4):281-282.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PPM1DID41803ch17q23.html


Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 1 ]
  Hereditary breast cancer


External links

Nomenclature
HGNC (Hugo)PPM1D   9277
LRG (Locus Reference Genomic)LRG_770
Cards
AtlasPPM1DID41803ch17q23
Entrez_Gene (NCBI)PPM1D  8493  protein phosphatase, Mg2+/Mn2+ dependent 1D
AliasesPP2C-DELTA; WIP1
GeneCards (Weizmann)PPM1D
Ensembl hg19 (Hinxton)ENSG00000170836 [Gene_View]  chr17:58677544-58743640 [Contig_View]  PPM1D [Vega]
Ensembl hg38 (Hinxton)ENSG00000170836 [Gene_View]  chr17:58677544-58743640 [Contig_View]  PPM1D [Vega]
ICGC DataPortalENSG00000170836
TCGA cBioPortalPPM1D
AceView (NCBI)PPM1D
Genatlas (Paris)PPM1D
WikiGenes8493
SOURCE (Princeton)PPM1D
Genetics Home Reference (NIH)PPM1D
Genomic and cartography
GoldenPath hg19 (UCSC)PPM1D  -     chr17:58677544-58743640 +  17q23.3   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)PPM1D  -     17q23.3   [Description]    (hg38-Dec_2013)
EnsemblPPM1D - 17q23.3 [CytoView hg19]  PPM1D - 17q23.3 [CytoView hg38]
Mapping of homologs : NCBIPPM1D [Mapview hg19]  PPM1D [Mapview hg38]
OMIM114480   605100   
Gene and transcription
Genbank (Entrez)AA326266 AK054573 AK299773 AK312902 AU280469
RefSeq transcript (Entrez)NM_003620
RefSeq genomic (Entrez)NC_000017 NC_018928 NG_023265 NT_010783 NW_004929407
Consensus coding sequences : CCDS (NCBI)PPM1D
Cluster EST : UnigeneHs.286073 [ NCBI ]
CGAP (NCI)Hs.286073
Alternative Splicing GalleryENSG00000170836
Gene ExpressionPPM1D [ NCBI-GEO ]   PPM1D [ EBI - ARRAY_EXPRESS ]   PPM1D [ SEEK ]   PPM1D [ MEM ]
Gene Expression Viewer (FireBrowse)PPM1D [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8493
GTEX Portal (Tissue expression)PPM1D
Protein : pattern, domain, 3D structure
UniProt/SwissProtO15297   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO15297  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO15297
Splice isoforms : SwissVarO15297
Catalytic activity : Enzyme3.1.3.16 [ Enzyme-Expasy ]   3.1.3.163.1.3.16 [ IntEnz-EBI ]   3.1.3.16 [ BRENDA ]   3.1.3.16 [ KEGG ]   
PhosPhoSitePlusO15297
Domaine pattern : Prosite (Expaxy)PPM_1 (PS01032)    PPM_2 (PS51746)   
Domains : Interpro (EBI)PP2C    PP2C_BS    PPM-type_phosphatase_dom   
Domain families : Pfam (Sanger)PP2C (PF00481)   
Domain families : Pfam (NCBI)pfam00481   
Domain families : Smart (EMBL)PP2Cc (SM00332)  
Conserved Domain (NCBI)PPM1D
DMDM Disease mutations8493
Blocks (Seattle)PPM1D
SuperfamilyO15297
Human Protein AtlasENSG00000170836
Peptide AtlasO15297
HPRD05482
IPIIPI00005782   IPI01014986   IPI00791057   
Protein Interaction databases
DIP (DOE-UCLA)O15297
IntAct (EBI)O15297
FunCoupENSG00000170836
BioGRIDPPM1D
STRING (EMBL)PPM1D
ZODIACPPM1D
Ontologies - Pathways
QuickGOO15297
Ontology : AmiGOG2/M transition of mitotic cell cycle  protein serine/threonine phosphatase activity  protein binding  nucleus  protein dephosphorylation  negative regulation of cell proliferation  cellular response to starvation  response to radiation  response to bacterium  peptidyl-threonine dephosphorylation  metal ion binding  mitogen-activated protein kinase binding  
Ontology : EGO-EBIG2/M transition of mitotic cell cycle  protein serine/threonine phosphatase activity  protein binding  nucleus  protein dephosphorylation  negative regulation of cell proliferation  cellular response to starvation  response to radiation  response to bacterium  peptidyl-threonine dephosphorylation  metal ion binding  mitogen-activated protein kinase binding  
Pathways : KEGGp53 signaling pathway   
NDEx NetworkPPM1D
Atlas of Cancer Signalling NetworkPPM1D
Wikipedia pathwaysPPM1D
Orthology - Evolution
OrthoDB8493
GeneTree (enSembl)ENSG00000170836
Phylogenetic Trees/Animal Genes : TreeFamPPM1D
HOVERGENO15297
HOGENOMO15297
Homologs : HomoloGenePPM1D
Homology/Alignments : Family Browser (UCSC)PPM1D
Gene fusions - Rearrangements
Fusion : MitelmanPGAP3/PPM1D [17q12/17q23.2]  [t(17;17)(q12;q23)]  
Fusion : MitelmanPPM1D/NUP85 [17q23.2/17q25.1]  [t(17;17)(q23;q25)]  
Fusion : MitelmanPPM1D/TRIM37 [17q23.2/17q22]  [t(17;17)(q22;q23)]  
Fusion : MitelmanSTXBP4/PPM1D [17q22/17q23.2]  [t(17;17)(q22;q23)]  
Fusion: TCGAPPM1D 17q23.2 NUP85 17q25.1 LGG
Fusion: TCGAPPM1D 17q23.2 TRIM37 17q22 BRCA
Fusion: TCGASTXBP4 17q22 PPM1D 17q23.2 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPPM1D [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PPM1D
dbVarPPM1D
ClinVarPPM1D
1000_GenomesPPM1D 
Exome Variant ServerPPM1D
ExAC (Exome Aggregation Consortium)PPM1D (select the gene name)
Genetic variants : HAPMAP8493
Genomic Variants (DGV)PPM1D [DGVbeta]
DECIPHER (Syndromes)17:58677544-58743640  ENSG00000170836
CONAN: Copy Number AnalysisPPM1D 
Mutations
ICGC Data PortalPPM1D 
TCGA Data PortalPPM1D 
Broad Tumor PortalPPM1D
OASIS PortalPPM1D [ Somatic mutations - Copy number]
Cancer Gene: CensusPPM1D 
Somatic Mutations in Cancer : COSMICPPM1D  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPPM1D
intOGen PortalPPM1D
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch PPM1D
DgiDB (Drug Gene Interaction Database)PPM1D
DoCM (Curated mutations)PPM1D (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PPM1D (select a term)
intoGenPPM1D
NCG5 (London)PPM1D
Cancer3DPPM1D(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM114480    605100   
Orphanet19054   
MedgenPPM1D
Genetic Testing Registry PPM1D
NextProtO15297 [Medical]
TSGene8493
GENETestsPPM1D
Huge Navigator PPM1D [HugePedia]
snp3D : Map Gene to Disease8493
BioCentury BCIQPPM1D
ClinGenPPM1D
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD8493
Chemical/Pharm GKB GenePA33605
Clinical trialPPM1D
Miscellaneous
canSAR (ICR)PPM1D (select the gene name)
Other databasehttp://genome.ewha.ac.kr/cgi-bin/ECquery.cgi?organism=human&query=PPM1D
Other databasehttp://modbase.compbio.ucsf.edu/modbase-cgi/model_details.cgi?queryfile=1173350594_2949&searchmode=default&displaymode=moddetail&referer=yes&snpflag=
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=PPM1D
Probes
Litterature
PubMed101 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePPM1D
EVEXPPM1D
GoPubMedPPM1D
iHOPPPM1D
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Nov 18 20:00:10 CET 2016

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