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.
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.
Description The PERP gene is of 19019 bases and localized on the minus strand. PERP encompasses three exons (NCBI, 2014).
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).
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).
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).
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).
Note The PERP gene expression was reported to be downregulated in uveal melanomas with high risk of metastasis (Paraoan et al., 2006).
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).
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).
Note It was shown that Perp mediates apoptosis in renal ischemia cells of mice models (Singaravelu et al., 2009).
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).
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).
Decreased PERP expression on peripheral blood mononuclear cells from patient with rheumatoid arthritis negatively correlates with disease activity.
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.
Loss of the p53/p63 target PERP is an early event in oral carcinogenesis and correlates with higher rate of local relapse.
Expression of p53-induced apoptosis effector PERP in primary uveal melanomas: downregulation is associated with aggressive type.
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