Abstract
A novel Death Effector Domain-containing protein was identified, DEDD2, which is closest in amino acid sequence homology to death effector domain-containing DNA-binding protein, DEDD. DEDD2 mRNA is expressed widely in adult human tissues with highest levels in liver, kidney, and peripheral blood leukocytes. DEDD2 interacts with FLIP, but not with Fas-associated death domain (FADD) or caspase-8. Overexpression of DEDD2 induces moderate apoptosis and results in substantial sensitization to apoptosis induced by Fas (CD95/APO-1), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo2L), or FADD. In contrast, Bax- or staurosporine-mediated cell death is not affected by expression of DEDD2. Fluorescence microscopy showed that overexpressed DEDD2 translocates to the nucleus, which is dependent on the presence of a bipartite nuclear localization signal in the DEDD2 protein. Mutagenesis studies revealed that the translocation of the DED of DEDD2 to the nucleus is essential for its pro-apoptotic activity. These findings suggest that DEDD2 is involved in the regulation of nuclear events mediated by the extrinsic apoptosis pathway.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Active Transport, Cell Nucleus
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Amino Acid Sequence
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Animals
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Apoptosis
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Arabidopsis Proteins*
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Blotting, Northern
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CASP8 and FADD-Like Apoptosis Regulating Protein
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COS Cells
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Carrier Proteins / biosynthesis*
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Carrier Proteins / chemistry*
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Carrier Proteins / metabolism
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Caspase 8
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Caspase 9
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Caspases / metabolism
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Cell Line
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Cell Nucleus / metabolism
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Cloning, Molecular
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Cytosol / metabolism
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DNA / metabolism
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DNA, Complementary / metabolism
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DNA-Binding Proteins / chemistry*
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Death Domain Receptor Signaling Adaptor Proteins
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Expressed Sequence Tags
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Fatty Acid Desaturases / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins*
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Microscopy, Fluorescence
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Molecular Sequence Data
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Nuclear Proteins / biosynthesis*
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Nuclear Proteins / chemistry*
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Plasmids / metabolism
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Precipitin Tests
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Protein Binding
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2*
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Homology, Amino Acid
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Time Factors
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Tissue Distribution
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bcl-2-Associated X Protein
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fas Receptor / metabolism
Substances
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Arabidopsis Proteins
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BAX protein, human
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Carrier Proteins
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DEDD protein, human
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DEDD2 protein, human
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DNA, Complementary
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DNA-Binding Proteins
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Death Domain Receptor Signaling Adaptor Proteins
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Intracellular Signaling Peptides and Proteins
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Nuclear Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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bcl-2-Associated X Protein
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fas Receptor
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DNA
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Fatty Acid Desaturases
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Fad7 protein, Arabidopsis
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CASP8 protein, human
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CASP9 protein, human
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Caspase 8
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Caspase 9
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Caspases