PERP (PERP, TP53 apoptosis effector)

2014-08-01   Hasan Huseyin Kazan , Can Özen , Mesut Muyan 


Atlas Image
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.


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.


Atlas Image
Boxes are exons. The lines are introns. Unshaded parts of the exon boxes are coding regions.


The PERP gene is of 19019 bases and localized on the minus strand. PERP encompasses three exons (NCBI, 2014).


4319 bp long mRNA; 582 bp long open reading frame (NM_022121.4).


No reported pseudogenes.



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).


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).


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).


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.


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

Entity name
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 name
Breast cancer
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 name
Squamous cell carcinoma (SCC)
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 name
Primary uveal melanoma
The PERP gene expression was reported to be downregulated in uveal melanomas with high risk of metastasis (Paraoan et al., 2006).
Entity name
Lung cancer
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 name
Rheumatoid arthritis (RA)
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 name
Renal ischemia
It was shown that Perp mediates apoptosis in renal ischemia cells of mice models (Singaravelu et al., 2009).
Entity name
Pemphigus vulgaris (PV)
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 name
Ankyloblepharon ectodermal dysplasia and cleft lip/palate (AEC) or Hay-Wells syndrome
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).


Pubmed IDLast YearTitleAuthors
107335302000PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family.Attardi LD et al
209759482010Loss of the p53/p63 regulated desmosomal protein Perp promotes tumorigenesis.Beaudry VG et al
195214072009Perp and pemphigus: a disease of desmosome destabilization.Bektas M et al
222368772011PERP gene therapy attenuates lung cancer xenograft via inducing apoptosis and suppressing VEGF.Chen K et al
190404202009P53 apoptosis mediator PERP: localization, function and caspase activation in uveal melanoma.Davies L et al
240660042013Decreased PERP expression on peripheral blood mononuclear cells from patient with rheumatoid arthritis negatively correlates with disease activity.Du Y et al
225156482012Deficiency of the p53/p63 target Perp alters mammary gland homeostasis and promotes cancer.Dusek RL et al
184384152008Stromal gene expression predicts clinical outcome in breast cancer.Finak G et al
236896842013Transmembrane 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 et al
113961422001Loss of heterozygosity of gene THW is frequently found in melanoma metastases.Hildebrandt T et al
157973842005Perp is a p63-regulated gene essential for epithelial integrity.Ihrie RA et al
212852472011PERP regulates enamel formation via effects on cell-cell adhesion and gene expression.Jheon AH et al
232175402013Loss of the p53/p63 target PERP is an early event in oral carcinogenesis and correlates with higher rate of local relapse.Kong CS et al
160616342005Mice lacking the p53/p63 target gene Perp are resistant to papilloma development.Marques MR et al
248652452014Developmental regulations of Perp in mice molar morphogenesis.Neupane S et al
191588432009Loss of the desmosomal protein perp enhances the phenotypic effects of pemphigus vulgaris autoantibodies.Nguyen B et al
155291762005Perp is required for tissue-specific cell survival during zebrafish development.Nowak M et al
167847422006Expression of p53-induced apoptosis effector PERP in primary uveal melanomas: downregulation is associated with aggressive type.Paraoan L et al
191583462009PERP, a p53 proapoptotic target, mediates apoptotic cell death in renal ischemia.Singaravelu K et al

Other Information

Locus ID:

NCBI: 64065
MIM: 609301
HGNC: 17637
Ensembl: ENSG00000112378


dbSNP: 64065
ClinVar: 64065
TCGA: ENSG00000112378


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
p53 signaling pathwayKEGGko04115
p53 signaling pathwayKEGGhsa04115
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Developmental BiologyREACTOMER-HSA-1266738
TP53 Regulates Transcription of Cell Death GenesREACTOMER-HSA-5633008
TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertainREACTOMER-HSA-6803205
Formation of the cornified envelopeREACTOMER-HSA-6809371

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA128406956fluorouracilChemicalClinicalAnnotation, VariantAnnotationassociatedPD
PA443560Breast NeoplasmsDiseaseClinicalAnnotation, VariantAnnotationassociatedPD
PA445113NeutropeniaDiseaseClinicalAnnotation, VariantAnnotationassociatedPD
PA449165cyclophosphamideChemicalClinicalAnnotation, VariantAnnotationassociatedPD
PA449476epirubicinChemicalClinicalAnnotation, VariantAnnotationassociatedPD


Pubmed IDYearTitleCitations
107335302000PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family.102
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
209759482010Loss of the p53/p63 regulated desmosomal protein Perp promotes tumorigenesis.32
204530002010A Large-scale genetic association study of esophageal adenocarcinoma risk.23
190404202009P53 apoptosis mediator PERP: localization, function and caspase activation in uveal melanoma.18
214515712011PERP expression stabilizes active p53 via modulation of p53-MDM2 interaction in uveal melanoma cells.16
208006032010Investigation of genetic susceptibility factors for human longevity - a targeted nonsynonymous SNP study.12
206280862010Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study.11
225156482012Deficiency of the p53/p63 target Perp alters mammary gland homeostasis and promotes cancer.10
193535882009Differential PERP regulation by TP63 mutants provides insight into AEC pathogenesis.9


Hasan Huseyin Kazan ; Can Özen ; Mesut Muyan

PERP (PERP, TP53 apoptosis effector)

Atlas Genet Cytogenet Oncol Haematol. 2014-08-01

Online version: