Sci. STKE, 12 December 2000
Apoptosis Transcription-Independent p53 Apoptosis Requires Caspase-8
The tumor suppressor p53 is involved in cell-cycle arrest and apoptosis in response to several intrinsic signals (DNA damage) and extrinsic signals (growth factor deprivation and hypoxia). Apoptosis triggered by p53 can occur through two mechanisms: one that requires the transcriptional activation of genes by p53 and one that is transcription-independent. Ding et al. explored the mechanisms by which p53 causes transcription-independent apoptosis (TI-apoptosis) using cell-free apoptosis assays and cell-based assays that relied on transfection experiments to trigger apoptosis by a mutant of p53 that lacked transcriptional regulatory activity. TI-apoptosis relied on the activation of caspase-8, which was found in a large (600-kD complex that did not contain the pro-apoptotic, death domain-containing protein FADD). In cells, TI-apoptosis required caspase-8 and caspase-9; however, in cell-free extracts, caspase-8 alone was sufficient to trigger cleavage of caspase-3. Finally, TI-apoptosis was blocked by cotransfection of the anti-apoptotic protein Bcl-2, and irradiation caused the cleavage of the pro-apoptotic protein BID. Thus, the authors propose that the p53-triggered TI-apoptosis involves the activation of caspase-8 during the formation of the novel 600-kD complex, which then leads to cleavage of BID and activation of the mitochondrial caspase-9 apoptotic pathway.
Ding, H.-F., Lin, Y.-L., McGill, G., Juo, P., Zhu, H., Blenis, J., Yuan, J., and Fisher, D.E. (2000) Essential role for caspase-8 in transcription-independent apoptosis triggered by p53. J. Biol. Chem. 275: 38905-38911. [Abstract] [Full Text]
Citation: Transcription-Independent p53 Apoptosis Requires Caspase-8. Sci. STKE 2000, tw7 (2000).
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