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PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis

Oncogene volume 18, pages 4409–4415 (1999)Cite this article

Abstract

PED/PEA-15 is a recently cloned 15 kDa protein possessing a death effector domain (DED). In MCF-7 and HeLa cells, a fivefold overexpression of PED/PEA-15 blocked FasL and TNFα apoptotic effects. This effect of PED overexpression was blocked by inhibition of PKC activity. In MCF-7 and HeLa cell lysates, PED/PEA-15 co-precipitated with both FADD and FLICE. PED/PEA-15-FLICE association was inhibited by overexpression of the wild-type but not of a DED-deletion mutant of FADD. Simultaneous overexpression of PED/PEA-15 with FADD and FLICE inhibited FADD-FLICE co-precipitation by threefold. Based on cleavage of the FLICE substrate PARP, this inhibitory effect was paralleled by a threefold decline in FLICE activation in response to TNF-α. TNFα, in turn, reduces PED association with the endogenous FADD and FLICE of the cells. Thus, PED/PEA-15 is an endogenous protein inhibiting FAS and TNFR1-mediated apoptosis. At least in part, this function may involve displacement of FADD-FLICE binding through the death effector domain of PED/PEA-15.

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Acknowledgements

The authors are grateful to Drs E Consiglio and G Vecchio for their continuous advice during the course of this work, and to GL Condorelli (Jefferson Medical College, Philadelphia) for technical advice and helpful discussion. We would also like to thank Drs B Trimarco for support, M Vitale for flow-cytometric quantitation of apoptosis, C Garbi for help with fluorescence microscopy, D Liguoro for the technical help and L Beguinot (DIBIT, HS Raffaele, Milan) for critical reading and discussion of the manuscript. This work was supported in part by the Biomed2 program of the European Community (Grant BMH4-CT-0751 to F Beguinot), a Telethon grant (Grant E.554) to F Beguinot, grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC) to F Beguinot and P Formisano, the Ministero dell’ Università e della Ricerca Scientifica, the CNR Target Project on Biotechnology and the Lilly and Novartis pharmaceuticals. M Caruso and G Vigliotta are recipients of fellowships of the Federazione Italiana per la Ricerca sul Cancro (FIRC). Almerinda Cafieri is the recipient of an award by Telethon Italy.

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  1. Dipartimento di Biologia e Patologia Cellulare e Molecolare ‘L. Califano’, Federico II University of Naples Medical School, Naples, Italy

    Gerolama Condorelli, Giovanni Vigliotta, Almerinda Cafieri, Alessandra Trencia, Paola Andalò, Francesco Oriente, Claudia Miele, Matilde Caruso, Pietro Formisano & Francesco Beguinot

  2. Centro di Endocrinologia ed Oncologia Sperimentale del C.N.R. ‘G. Salvatore’, Federico II University of Naples Medical School, Naples, Italy

    Gerolama Condorelli, Giovanni Vigliotta, Almerinda Cafieri, Alessandra Trencia, Paola Andalò, Francesco Oriente, Claudia Miele, Matilde Caruso, Pietro Formisano & Francesco Beguinot

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  1. Gerolama Condorelli
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Condorelli, G., Vigliotta, G., Cafieri, A. et al. PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis. Oncogene 18, 4409–4415 (1999). https://doi.org/10.1038/sj.onc.1202831

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