{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPERP was first characterized as a p53‐inducible gene that functions as an effector of apoptosis. Its expression is specifically up‐regulated during p53‐mediated cell death rather than cell cycle arrest, and it acts as a tetraspan membrane protein capable of triggering caspase‐dependent apoptotic pathways – particularly via the extrinsic, caspase‐8–mediated route. In uveal melanoma cells, for example, PERP induction leads to receptor‐mediated apoptosis and further reinforces p53 activation by enhancing its nuclear localization and transcriptional activity, thereby establishing a positive feedback loop. In aggressive tumors such as certain pituitary adenomas, restoration of PERP expression suppresses colony formation and promotes apoptosis, underscoring its tumor‐suppressive function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in apoptosis, PERP is a critical structural component of desmosomes, thereby ensuring robust cell–cell adhesion, particularly in stratified epithelia. Disruption of PERP function via autoantibody–induced internalization—as observed in pemphigus vulgaris—or through mutations that compromise its incorporation into desmosomes, leads to impaired epithelial integrity and blistering phenotypes. Moreover, mutations in TP63 that fail to properly transactivate PERP have been implicated in disorders such as AEC syndrome, while genetic defects in PERP itself cause forms of keratoderma and erythrokeratoderma. In mouse models, loss of PERP results in a selective downregulation of desmosomal proteins, driving both local inflammation and tumor progression in squamous cell carcinomas."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional evidence indicates that PERP’s functions extend to modulating tissue homeostasis and inflammatory responses. In the mammary gland, PERP—regulated by p63—appears to be involved in maintaining epithelial architecture. In peripheral blood mononuclear cells from rheumatoid arthritis patients, decreased PERP expression correlates with heightened disease activity, suggesting a role in controlling cell survival in immune settings. Furthermore, microbial pathogens such as Salmonella exploit host PERP: the bacterial effector proteins SipA and SipC interact with and re‐distribute PERP at the apical membrane of epithelial cells, thereby influencing proinflammatory signaling. Finally, in pulmonary arterial smooth muscle cells, PERP is targeted by miR-629 under hypoxic conditions; its down‐regulation promotes cell proliferation and migration that may contribute to disease pathology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "L D Attardi, E E Reczek, C Cosmas, et al. 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