Apoptosis induced by the nuclear death domain protein p84N5 is inhibited by association with Rb protein.
Rb protein inhibits both cell cycle progression and apoptosis. Interaction of specific cellular proteins, including E2F1, with Rb C-terminal domains mediates cell cycle regulation. In contrast, the nuclear N5 protein associates with an Rb N-terminal domain with unknown function. The N5 protein contains a region of sequence similarity to the death domain of proteins involved in apoptotic signaling. We demonstrate here that forced N5 expression potently induces apoptosis in several tumor cell lines. Mutation of conserved residues within the death domain homology compromise N5-induced apoptosis, suggesting that it is required for normal function. Endogenous N5 protein is specifically altered in apoptotic cells treated with ionizing radiation. Furthermore, dominant interfering death domain mutants compromise cellular responses to ionizing radiation. Finally, physical association with Rb protein inhibits N5-induced apoptosis. We propose that N5 protein plays a role in the regulation of apoptosis and that Rb directly coordinates cell proliferation and apoptosis by binding specific proteins involved in each process through distinct protein binding domains.
Doostzadeh-Cizeron
J
J
Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Evans
R
R
Yin
S
S
Goodrich
D W
DW
D000595:Amino Acid Sequence; D017209:Apoptosis; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002460:Cell Line; D053938:DNA Fragmentation; D004268:DNA-Binding Proteins; D005455:Fluorescent Antibody Technique; D005720:Gamma Rays; D006801:Humans; D008845:Microinjections; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; C400546:THOC1 protein, human; D019311:Staurosporine