title: PERP expression stabilizes active p53 via modulation of p53-MDM2 interaction in uveal melanoma cells.
abstract: The activation and regulation of target genes by the tumour-suppressor p53 dictates the fate of a cell, with cell cycle arrest or apoptosis being two distinct outcomes. PERP (p53 apoptosis effector related to PMP-22), a p53 transcriptional target, is induced specifically during apoptosis but not cell cycle arrest. Downregulation of PERP is associated with the aggressive, monosomy 3-type of uveal melanoma (UM), the most common primary intraocular tumour in adults, and increased PERP expression has a pro-apoptotic effect in UM cells. Here, we identify a novel effect of PERP expression, as elevated PERP protein positively influences active levels of its own transcriptional regulator, p53. Using fluorescent fusion proteins of PERP, p53 and MDM2, we demonstrate in single living UM cells that PERP expression significantly enhances p53 activity and its nuclear localization, increases p53-dependent transcription (including that of MDM2) while allowing oscillatory nucleo-cytoplasmic shuttling of p53/MDM2 complexes. Phosphorylation of p53 serine residues that interfere with the interaction between p53 and its negative regulator MDM2 and enhance pro-apoptotic gene transcription also occurs subsequent to PERP expression. These results implicate a role for PERP in amplifying functional p53 levels that promote p53-dependent apoptosis, and reveal a potential target for exploitation in enhancing p53 activity.
authors: Department of Eye and Vision Sciences, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK.
authors: L
authors: L
authors: Davies
authors: D
authors: D
authors: Spiller
authors: M R H
authors: MR
authors: White
authors: I
authors: I
authors: Grierson
authors: L
authors: L
authors: Paraoan
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D055550:Protein Stability; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014604:Uveal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000098943:Uveal Melanoma
chemical_list: D008565:Membrane Proteins; C416404:PERP protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2