title: Expression of p53-induced apoptosis effector PERP in primary uveal melanomas: downregulation is associated with aggressive type.
abstract: Expression of PERP (p53 apoptosis effector related to PMP-22) was investigated in primary uveal melanomas and its variation was analyzed in relation to clinico-pathological and cytogenetical characteristics of these tumors. The transcriptional level of PERP gene was measured by quantitative real-time RT-PCR in 26 uveal melanomas with known chromosomes 3 and 8 status. PERP protein levels were assessed by Western blot analysis of 22 fresh-frozen tumors and by immunohistochemical analysis of 16 paraffin-embedded tumor specimens. Differential expression of PERP was identified in primary choroidal melanoma specimens, both at transcriptional and protein level. Reduced PERP mRNA level was significantly associated with monosomy 3 (two-way ANOVA and t-test, p=0.004) but not with gains in chromosome 8. Transcriptional downregulation of PERP did not present a statistically significant association with ciliary body involvement, size, PAS-positive loops or cell type. Immunoblotting and immunohistochemistry further demonstrated significantly reduced PERP protein level in monosomy 3 melanomas, as compared with disomy 3 tumors. The altered expression of PERP highlighted this apoptosis-specific target of p53 as a possible contributor to apoptosis in uveal melanoma with PERP downregulation being particularly relevant to the aggressive (monosomy 3) type of uveal melanoma. As PERP is a novel type of p53 effector that is likely to stimulate apoptosis through a mechanism distinct from that of Bcl-2-related mitochondrial effectors, further elucidation of its role in uveal melanoma pathogenesis will assist in the design of novel therapeutic approaches aimed at increasing the rate of apoptosis in this tumor.
authors.affiliation: Unit of Ophthalmology, School of Clinical Sciences, University of Liverpool, UCD Building, Daulby Street, Liverpool L69 3GA, UK. luminita.paraoan@liverpool.ac.uk
authors.forename: Luminita
authors.initials: L
authors.lastname: Paraoan
authors.forename: Donna
authors.initials: D
authors.lastname: Gray
authors.forename: Paul
authors.initials: P
authors.lastname: Hiscott
authors.forename: Bahram
authors.initials: B
authors.lastname: Ebrahimi
authors.forename: Bertil
authors.initials: B
authors.lastname: Damato
authors.forename: Ian
authors.initials: I
authors.lastname: Grierson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D015153:Blotting, Western / Q000379:methods; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009006:Monosomy; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014158:Transcription, Genetic; D014604:Uveal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D008565:Membrane Proteins; D009363:Neoplasm Proteins; C416404:PERP protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm