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PERP (PERP, TP53 apoptosis effector)

Written2014-08Hasan Hüseyin Kazan, Can Özen, Mesut Muyan
Department of Biotechnology, Middle East Technical University, Ankara, Turkey (HHK); Department of Biotechnology, Central Laboratory for Molecular Biology, Biotechnology R, D Center, Middle East Technical University, Ankara, Turkey (CO); Department of Biological Sciences, Middle East Technical University, Ankara, Turkey (MM)

Abstract PERP is a p53/p63-regulated gene encoding a desmosomal protein that plays a critical role in stratified epithelial development, cell adhesion and tumor suppression.

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Identity

Alias_symbol (synonym)PIGPC1
dJ496H19.1
KCP1
THW
KRTCAP1
HGNC (Hugo) PERP
LocusID (NCBI) 64065
Atlas_Id 50465
Location 6q23.3  [Link to chromosome band 6q23]
Location_base_pair Starts at 138409642 and ends at 138428660 bp from pter ( according to hg19-Feb_2009)  [Mapping PERP.png]
Local_order From centromere to telomere: LOC100130476, TNFAIP3, RPSAP42, PERP, KIAA1244, PBOV1, MARCKSL1P2.
 
  Local order of PERP is shown together with leading and subsequent genes on chromosome 6. The direction of arrows indicates transcriptional directions on the chromosome and arrow sizes approximate gene sizes.
Fusion genes
(updated 2016)
MAP3K5 (6q23.3) / PERP (6q23.3)PERP (6q23.3) / DDX27 (20q13.13)PERP (6q23.3) / METAP1 (4q23)
PERP (6q23.3) / SLC2A1 (1p34.2)PERP (6q23.3) / SSBP1 (7q34)

DNA/RNA

 
  Boxes are exons. The lines are introns. Unshaded parts of the exon boxes are coding regions.
Description The PERP gene is of 19019 bases and localized on the minus strand. PERP encompasses three exons (NCBI, 2014).
Transcription 4319 bp long mRNA; 582 bp long open reading frame (NM_022121.4).
Pseudogene No reported pseudogenes.

Protein

Description PERP encodes a 193 amino acid long tetraspan membrane protein (Attardi et al., 2000). Perp has a molecular mass of 21 kDa with an isoelectric point of 6.68 (Franke et al., 2013).
Expression PERP is expressed in the tongue mucosa, cornea, heart, lung (Chen et al., 2011) simple, columnar, complex, transitional and stratified epithelia of human, bovine, porcine and murine (Franke et al., 2013) and teeth (Jheon et al., 2011; Neupane et al., 2014). PERP is also expressed in the primary choroidal melanoma (Paraoan et al., 2006) and in cell lines derived from breast, prostate, colon, cervix and pancreas tumors (Hildebrandt et al., 2001).
Localisation Perp exhibits a punctuated pattern of localization at the plasma membrane and interdesmosomal regions (Franke et al., 2013) and colocalizes with desmosomal components (Attardi et al., 2000; Davies et al., 2009; Singaravelu et al., 2009). Perp is also suggested to localize at the perinuclear region and endoplasmic reticulum/golgi apparatus in primary uveal melanoma (UM) cells (Davies et al., 2009).
Function PERP is a transcriptional target of p53 and p63 transcription factors acting alone or in concert to homeodynamically modulate cellular responses. The expression of PERP appears to be independent of p53 in embryogenesis but is dependent upon p63. The interaction of p53 or p63 with several response elements of varying affinities on the PERP locus is responsible for the PERP expression. The regulation of PERP transcription by p63 in epithelial-specific manner during embryogenesis is critical for the stratified epithelial development through functions of Perp at desmosomes (Attardi et al., 2000; Ihrie et al., 2005). The absence of Perp as studied in a PERP knockout mouse model is manifested as defects in the assembly and maintenance of desmosomes (Ihrie et al., 2005). Perp is also shown to participate in skin and notochord development of zebrafish (Nowak et al., 2005). The mediation of PERP expression by p53 results in apoptosis independent of cell cycle arrest. The expression of PERP is shown to increase during apoptosis, but not upon induced G1 arrest in mouse embryonic fibroblasts (Attardi et al., 2000). Induction of PERP expression induces apoptosis through the activation of caspase-8 in primary UM cell lines (Davies et al., 2009). Similarly, the overexpression of PERP at the outer medullary proximal tubular cells of ischemic kidneys in response to hypoxia appears to augment apoptosis by inducing mitochondrial permeability and cytochrome c release as well as by activating apoptosis-inducing factor (AIF) and caspase 9 proteins (Singaravelu et al., 2009).
These findings collectively indicate that Perp is an important mediator of stratified epithelial development, cell adhesion and apoptosis through desmosomal activities.
Homology Perp shares amino acid sequence similarities with peripheral myelin protein 22/growth arrest specific 3 (PMP-22/gas3) tetraspan membrane protein family, which is associated with growth regulation (Attardi et al., 2000).

Implicated in

Note
Entity Papilloma
Note Papilloma refers to an exophytically growing benign epithelial tumor. In studies using a two-step skin carcinogenesis mice model system, it was shown that mice lacking PERP expression in the skin are resistant to papilloma development. It appears that the lack of Perp impairs cell adhesion as a result of aberrant desmosome assembly, thereby diminishing tumor development (Marques et al., 2005).
  
Entity Breast cancer
Note Using a laser capture microdissection approach in tumor stroma from primary breast tumors, it was reported that PERP is one of repressed genes in samples of the poor outcome cohort (Finak et al., 2008). This is consistent with findings that the expression of PERP is reduced in breast cancer cell lines. Experimental studies using a mouse mammary cancer model further reveal that Perp plays an important role in mammary gland homeostasis by affecting desmosome numbers and/or integrity in the mammary epithelium and in mammary tumor suppression by modulating microenvironment (Dusek et al., 2012).
  
Entity Squamous cell carcinoma (SCC)
Note The SCC, the second-most common skin cancer, is a malignant proliferation of the keratinocyte of the epidermis (Schwartz, 1988). It was reported that the expression of PERP is downregulated during SCC progression. Moreover, Perp deficiency appeared to promote SCC in a PERP knockout mouse model for human SCC (Beaudry et al., 2010). Consistent with these observations, the loss of PERP expression is reported to correlate with the progression of oral cavity SCC with increased local relapse (Kong et al., 2013).
  
Entity Primary uveal melanoma
Note The PERP gene expression was reported to be downregulated in uveal melanomas with high risk of metastasis (Paraoan et al., 2006).
  
Entity Lung cancer
Note It was shown that the PERP gene introduction as a gene therapy approach induces apoptosis in lung cancer xenografts in mice by reducing xenograft volume and preventing angiogenesis through the activation of pro-apoptotic caspase-3 cascade and the suppression of vascular endothelial growth factor expression. The introduction of PERP was also observed to lead to an enhanced activity of the second mitochondria-derived activator of caspase (Smac) cascade (Chen et al., 2011).
  
Entity Rheumatoid arthritis (RA)
Note It was reported that PERP mRNA levels in peripheral blood mononuclear cells from patients with RA are significantly lower than those of healthy subjects (Du et al., 2013).
  
Entity Renal ischemia
Note It was shown that Perp mediates apoptosis in renal ischemia cells of mice models (Singaravelu et al., 2009).
  
Entity Pemphigus vulgaris (PV)
Note PV is an autoimmune disease with the loss of cell-cell adhesion in the epidermis induced by desmoglein (a desmosomal protein)-specific autoantibodies (Bektas and Rubenstein, 2009). In studies using human keratinocyte cultures, it was demonstrated that PV autoantibodies hinder the localization of Perp at the membrane and induce its internalization with desmosomal cadherin desmoglein 3 (DSG3) through an endosomal pathway resulting in Perp degradation. Furthermore, PERP deficiency in PERP-/- keratinocytes was found to enhance pathogenic effects of PV autoantibodies (Nguyen et al., 2009).
  
Entity Ankyloblepharon ectodermal dysplasia and cleft lip/palate (AEC) or Hay-Wells syndrome
Note AEC is an autosomal dominant disorder characterized by the abnormal development of ectodermal tissues including the skin, hair, nails, teeth, and sweat glands. A subset of AEC patients was found to show an aberrant PERP expression in skin biopsies. This finding suggests that dysregulation of the PERP gene expression contributes to the pathogenesis of AEC (Beaudry et al., 2009).
  

Bibliography

PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family.
Attardi LD, Reczek EE, Cosmas C, Demicco EG, McCurrach ME, Lowe SW, Jacks T.
Genes Dev. 2000 Mar 15;14(6):704-18.
PMID 10733530
 
Loss of the p53/p63 regulated desmosomal protein Perp promotes tumorigenesis.
Beaudry VG, Jiang D, Dusek RL, Park EJ, Knezevich S, Ridd K, Vogel H, Bastian BC, Attardi LD.
PLoS Genet. 2010 Oct 21;6(10):e1001168. doi: 10.1371/journal.pgen.1001168.
PMID 20975948
 
Perp and pemphigus: a disease of desmosome destabilization.
Bektas M, Rubenstein DS.
J Invest Dermatol. 2009 Jul;129(7):1606-8. doi: 10.1038/jid.2009.117.
PMID 19521407
 
PERP gene therapy attenuates lung cancer xenograft via inducing apoptosis and suppressing VEGF.
Chen K, Luo Z, Li Z, Liu Y, Zhao Q.
Cancer Biol Ther. 2011 Dec 15;12(12):1114-9. doi: 10.4161/cbt.12.12.18435. Epub 2011 Dec 15.
PMID 22236877
 
P53 apoptosis mediator PERP: localization, function and caspase activation in uveal melanoma.
Davies L, Gray D, Spiller D, White MR, Damato B, Grierson I, Paraoan L.
J Cell Mol Med. 2009 Aug;13(8B):1995-2007. doi: 10.1111/j.1582-4934.2008.00590.x.
PMID 19040420
 
Decreased PERP expression on peripheral blood mononuclear cells from patient with rheumatoid arthritis negatively correlates with disease activity.
Du Y, Deng L, Li Y, Gan L, Wang Y, Shi G.
Clin Dev Immunol. 2013;2013:256462. doi: 10.1155/2013/256462. Epub 2013 Aug 26.
PMID 24066004
 
Deficiency of the p53/p63 target Perp alters mammary gland homeostasis and promotes cancer.
Dusek RL, Bascom JL, Vogel H, Baron S, Borowsky AD, Bissell MJ, Attardi LD.
Breast Cancer Res. 2012 Apr 20;14(2):R65.
PMID 22515648
 
Stromal gene expression predicts clinical outcome in breast cancer.
Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, Chen H, Omeroglu G, Meterissian S, Omeroglu A, Hallett M, Park M.
Nat Med. 2008 May;14(5):518-27. doi: 10.1038/nm1764. Epub 2008 Apr 27.
PMID 18438415
 
Transmembrane protein PERP is a component of tessellate junctions and of other junctional and non-junctional plasma membrane regions in diverse epithelial and epithelium-derived cells.
Franke WW, Heid H, Zimbelmann R, Kuhn C, Winter-Simanowski S, Dorflinger Y, Grund C, Rickelt S.
Cell Tissue Res. 2013 Jul;353(1):99-115. doi: 10.1007/s00441-013-1645-3. Epub 2013 May 21.
PMID 23689684
 
Loss of heterozygosity of gene THW is frequently found in melanoma metastases.
Hildebrandt T, van Dijk MC, van Muijen GN, Weidle UH.
Anticancer Res. 2001 Mar-Apr;21(2A):1071-80.
PMID 11396142
 
Perp is a p63-regulated gene essential for epithelial integrity.
Ihrie RA, Marques MR, Nguyen BT, Horner JS, Papazoglu C, Bronson RT, Mills AA, Attardi LD.
Cell. 2005 Mar 25;120(6):843-56.
PMID 15797384
 
PERP regulates enamel formation via effects on cell-cell adhesion and gene expression.
Jheon AH, Mostowfi P, Snead ML, Ihrie RA, Sone E, Pramparo T, Attardi LD, Klein OD.
J Cell Sci. 2011 Mar 1;124(Pt 5):745-54. doi: 10.1242/jcs.078071. Epub 2011 Feb 1.
PMID 21285247
 
Loss of the p53/p63 target PERP is an early event in oral carcinogenesis and correlates with higher rate of local relapse.
Kong CS, Cao H, Kwok S, Nguyen CM, Jordan RC, Beaudry VG, Attardi LD, Le QT.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2013 Jan;115(1):95-103. doi: 10.1016/j.oooo.2012.10.017.
PMID 23217540
 
Mice lacking the p53/p63 target gene Perp are resistant to papilloma development.
Marques MR, Horner JS, Ihrie RA, Bronson RT, Attardi LD.
Cancer Res. 2005 Aug 1;65(15):6551-6.
PMID 16061634
 
Developmental regulations of Perp in mice molar morphogenesis.
Neupane S, Sohn WJ, Rijal G, Lee YJ, Lee S, Yamamoto H, An CH, Cho SW, Lee Y, Shin HI, Kwon TY, Kim JY.
Cell Tissue Res. 2014 Oct;358(1):109-21. doi: 10.1007/s00441-014-1908-7. Epub 2014 May 28.
PMID 24865245
 
Loss of the desmosomal protein perp enhances the phenotypic effects of pemphigus vulgaris autoantibodies.
Nguyen B, Dusek RL, Beaudry VG, Marinkovich MP, Attardi LD.
J Invest Dermatol. 2009 Jul;129(7):1710-8. doi: 10.1038/jid.2008.419. Epub 2009 Jan 22.
PMID 19158843
 
Perp is required for tissue-specific cell survival during zebrafish development.
Nowak M, Koster C, Hammerschmidt M.
Cell Death Differ. 2005 Jan;12(1):52-64.
PMID 15529176
 
Expression of p53-induced apoptosis effector PERP in primary uveal melanomas: downregulation is associated with aggressive type.
Paraoan L, Gray D, Hiscott P, Ebrahimi B, Damato B, Grierson I.
Exp Eye Res. 2006 Oct;83(4):911-9. Epub 2006 Jun 19.
PMID 16784742
 
Skin cancer recognition and management. Squamous Cell Carcinoma.
Schwartz RA.
Springer New York;1988:36-47.
 
PERP, a p53 proapoptotic target, mediates apoptotic cell death in renal ischemia.
Singaravelu K, Devalaraja-Narashimha K, Lastovica B, Padanilam BJ.
Am J Physiol Renal Physiol. 2009 Apr;296(4):F847-58. doi: 10.1152/ajprenal.90438.2008. Epub 2009 Jan 21.
PMID 19158346
 

Citation

This paper should be referenced as such :
Kazan HH, iÖzen C, Muyan M
PERP (PERP, TP53 apoptosis effector);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/PERPID50465ch6q23.html


External links

Nomenclature
HGNC (Hugo)PERP   17637
Cards
AtlasPERPID50465ch6q23
Entrez_Gene (NCBI)PERP  64065  PERP, TP53 apoptosis effector
AliasesKCP1; KRTCAP1; PIGPC1; THW; 
dJ496H19.1
GeneCards (Weizmann)PERP
Ensembl hg19 (Hinxton)ENSG00000112378 [Gene_View]  chr6:138409642-138428660 [Contig_View]  PERP [Vega]
Ensembl hg38 (Hinxton)ENSG00000112378 [Gene_View]  chr6:138409642-138428660 [Contig_View]  PERP [Vega]
ICGC DataPortalENSG00000112378
TCGA cBioPortalPERP
AceView (NCBI)PERP
Genatlas (Paris)PERP
WikiGenes64065
SOURCE (Princeton)PERP
Genetics Home Reference (NIH)PERP
Genomic and cartography
GoldenPath hg19 (UCSC)PERP  -     chr6:138409642-138428660 -  6q24   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)PERP  -     6q24   [Description]    (hg38-Dec_2013)
EnsemblPERP - 6q24 [CytoView hg19]  PERP - 6q24 [CytoView hg38]
Mapping of homologs : NCBIPERP [Mapview hg19]  PERP [Mapview hg38]
OMIM609301   
Gene and transcription
Genbank (Entrez)AF317550 AJ251830 AK074585 AK075082 AK093516
RefSeq transcript (Entrez)NM_022121
RefSeq genomic (Entrez)NC_000006 NC_018917 NT_025741 NW_004929328
Consensus coding sequences : CCDS (NCBI)PERP
Cluster EST : UnigeneHs.201446 [ NCBI ]
CGAP (NCI)Hs.201446
Alternative Splicing GalleryENSG00000112378
Gene ExpressionPERP [ NCBI-GEO ]   PERP [ EBI - ARRAY_EXPRESS ]   PERP [ SEEK ]   PERP [ MEM ]
Gene Expression Viewer (FireBrowse)PERP [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)64065
GTEX Portal (Tissue expression)PERP
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ96FX8   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ96FX8  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ96FX8
Splice isoforms : SwissVarQ96FX8
PhosPhoSitePlusQ96FX8
Domains : Interpro (EBI)P53_induced    PMP22/EMP/MP20/Claudin   
Domain families : Pfam (Sanger)PMP22_Claudin (PF00822)   
Domain families : Pfam (NCBI)pfam00822   
Conserved Domain (NCBI)PERP
DMDM Disease mutations64065
Blocks (Seattle)PERP
SuperfamilyQ96FX8
Human Protein AtlasENSG00000112378
Peptide AtlasQ96FX8
HPRD17836
IPIIPI00293189   IPI00939465   
Protein Interaction databases
DIP (DOE-UCLA)Q96FX8
IntAct (EBI)Q96FX8
FunCoupENSG00000112378
BioGRIDPERP
STRING (EMBL)PERP
ZODIACPERP
Ontologies - Pathways
QuickGOQ96FX8
Ontology : AmiGOdesmosome organization  mitochondrion  Golgi apparatus  plasma membrane  integral component of plasma membrane  Notch signaling pathway  cell junction  desmosome  heterotypic cell-cell adhesion  regulation of apoptotic process  positive regulation of proteolysis  intrinsic apoptotic signaling pathway by p53 class mediator  amelogenesis  activation of cysteine-type endopeptidase activity  cell-cell adhesion  
Ontology : EGO-EBIdesmosome organization  mitochondrion  Golgi apparatus  plasma membrane  integral component of plasma membrane  Notch signaling pathway  cell junction  desmosome  heterotypic cell-cell adhesion  regulation of apoptotic process  positive regulation of proteolysis  intrinsic apoptotic signaling pathway by p53 class mediator  amelogenesis  activation of cysteine-type endopeptidase activity  cell-cell adhesion  
Pathways : KEGGp53 signaling pathway   
NDEx NetworkPERP
Atlas of Cancer Signalling NetworkPERP
Wikipedia pathwaysPERP
Orthology - Evolution
OrthoDB64065
GeneTree (enSembl)ENSG00000112378
Phylogenetic Trees/Animal Genes : TreeFamPERP
HOVERGENQ96FX8
HOGENOMQ96FX8
Homologs : HomoloGenePERP
Homology/Alignments : Family Browser (UCSC)PERP
Gene fusions - Rearrangements
Fusion : MitelmanMAP3K5/PERP [6q23.3/6q23.3]  [t(6;6)(q23;q23)]  
Fusion : MitelmanPERP/DDX27 [6q23.3/20q13.13]  [t(6;20)(q23;q13)]  
Fusion: TCGAMAP3K5 6q23.3 PERP 6q23.3 BLCA
Fusion: TCGAPERP 6q23.3 DDX27 20q13.13 LUSC
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerPERP [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)PERP
dbVarPERP
ClinVarPERP
1000_GenomesPERP 
Exome Variant ServerPERP
ExAC (Exome Aggregation Consortium)PERP (select the gene name)
Genetic variants : HAPMAP64065
Genomic Variants (DGV)PERP [DGVbeta]
DECIPHER (Syndromes)6:138409642-138428660  ENSG00000112378
CONAN: Copy Number AnalysisPERP 
Mutations
ICGC Data PortalPERP 
TCGA Data PortalPERP 
Broad Tumor PortalPERP
OASIS PortalPERP [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICPERP  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDPERP
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch PERP
DgiDB (Drug Gene Interaction Database)PERP
DoCM (Curated mutations)PERP (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)PERP (select a term)
intoGenPERP
NCG5 (London)PERP
Cancer3DPERP(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM609301   
Orphanet
MedgenPERP
Genetic Testing Registry PERP
NextProtQ96FX8 [Medical]
TSGene64065
GENETestsPERP
Huge Navigator PERP [HugePedia]
snp3D : Map Gene to Disease64065
BioCentury BCIQPERP
ClinGenPERP
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD64065
Chemical/Pharm GKB GenePA134944221
Clinical trialPERP
Miscellaneous
canSAR (ICR)PERP (select the gene name)
Probes
Litterature
PubMed31 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMinePERP
EVEXPERP
GoPubMedPERP
iHOPPERP
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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