P53 apoptosis mediator PERP: localization, function and caspase activation in uveal melanoma

Lyndsay Davies, Donna Gray, Dave Spiller, Mike R H White, Bertil Damato, Ian Grierson, Luminita Paraoan

    Research output: Contribution to journalArticlepeer-review

    Abstract

    p53 apoptosis effector related to PMP-22 (PERP) is a transcriptional target gene of p53 tumour suppressor that is specifically induced during apoptosis and not during cell cycle arrest. In primary uveal melanoma (UM), the most common intraocular malignancy in adults that has a reportedly unaffected signalling pathway upstream of and including p53, PERP expression is down-regulated in the metastatic monosomy 3-type tumours, compared with the less aggressive disomy 3-type tumours. Here, we demonstrate experimentally, by the use of full-length PERP-green fluorescent protein (GFP) fusions and real-time confocal microscopy, the intracellular targeting and plasma membrane localization of PERP in living UM cells and show that expression of PERP induces caspase-mediated apoptosis in UM cells. Induction of PERP expression in GFP-PERP-transfected UM cells leads to increased levels of cleaved caspase-8 forms, as well as to reduction of its full-length substrate Bid, but not to detectable processing of caspase-9. The levels of mature caspase-8, -9 and -3 proteins significantly correlate with PERP expression levels in primary UMs. Transcriptional profiling of PERP and caspase-8 in tumour specimens indicates that the positive association of PERP and caspase-8 proteins is a consequence of post-translational processing, most likely at the level of caspase-8 cleavage, and not of increased transcription of pro-caspase-8. We conclude that PERP expression leads to activation of an extrinsic receptor-mediated apoptotic pathway, with a possible subsequent engagement of the intrinsic apoptotic pathway. The findings underline the apoptotic pathway mediated by PERP as a critical mechanism employed by UM tumours to modulate susceptibility to apoptosis. © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
    Original languageEnglish
    Pages (from-to)1995-2007
    Number of pages12
    JournalJournal of cellular and molecular medicine
    Volume13
    Issue number8 B
    DOIs
    Publication statusPublished - Aug 2009

    Keywords

    • Apoptosis
    • Caspase
    • Green fluorescent protein
    • P53
    • PERP
    • Transfection
    • Uveal melanoma

    Fingerprint

    Dive into the research topics of 'P53 apoptosis mediator PERP: localization, function and caspase activation in uveal melanoma'. Together they form a unique fingerprint.

    Cite this