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

Oncogene. 1999 Aug 5;18(31):4409-15. doi: 10.1038/sj.onc.1202831.

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 TNFalpha 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-alpha. TNFalpha, 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Antigens, CD / physiology*
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Breast Neoplasms
  • Carrier Proteins / metabolism
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism
  • Fas-Associated Death Domain Protein
  • Female
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mutagenesis, Site-Directed
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein Biosynthesis
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Receptors, Tumor Necrosis Factor / physiology*
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Proteins / metabolism
  • Sequence Deletion
  • Transfection
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / pharmacology
  • fas Receptor / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • Carrier Proteins
  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • Intracellular Signaling Peptides and Proteins
  • PEA15 protein, human
  • Phosphoproteins
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Protein Kinase C
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 8
  • Caspase 9
  • Caspases