The p53 tumor suppressor promotes cell cycle arrest or apoptosis in response to diverse stress stimuli. p53-mediated cell death depends in large part on transcriptional up-regulation of target genes. One of these targets, P53-induced protein with a death domain (PIDD), was shown to function as a mediator of p53-dependent apoptosis. Here we show that PIDD is a cytoplasmic protein, and that PIDD-induced apoptosis and growth suppression in embryonic fibroblasts depend on the adaptor protein receptorinteracting protein (RIP)-associated ICH-1͞CED-3 homologous protein with a death domain (RAIDD). We provide evidence that PIDD-induced cell death is associated with the early activation of caspase-2 and later activation of caspase-3 and -7. Our results also show that caspase-2 ؊/؊ , in contrast to RAIDD ؊/؊ , mouse embryonic fibroblasts, are only partially resistant to PIDD. Our findings suggest that caspase-2 contributes to PIDD-mediated cell death, but that it is not the sole effector of this pathway.caspase-2 T he tumor suppressor p53 is a sequence-specific transcription factor that promotes cell cycle arrest or apoptosis in response to cellular stress (1). Transcriptional activation of the p21 WAF1 cyclin-dependent kinase inhibitor plays a key role in the induction of cell cycle arrest by p53 (2). p53-dependent apoptosis is regulated, at least in part, by transcriptional activation of its target genes (3), and this process highly depends on cytochrome c release and the Apaf-1͞caspase-9 activation pathway (4, 5). Although a number of candidate p53-effector molecules have been reported, it is yet unclear whether each contributes a part of the full response, or whether specific subsets of these genes are required for death in different cell types or in response to different signals (3).Among the identified apoptotic effectors of p53, P53-induced protein with a death domain (PIDD)͞leucine-rich DD (LRDD) is a 915-aa protein in mice (910 aa in humans) containing seven tandem LR repeats in the N terminus and a DD in the C terminus (6, 7). The dual domain structure of PIDD suggests that it may function as a key adapter protein that links additional components of the p53 apoptosis pathway. Using the method of differential display, PIDD was identified as a p53-up-regulated gene in a p53-null Friend-virus-transformed mouse erythroleukemia cell line (DP16.1͞p53ts) that stably expresses a temperature-sensitive (ts) Trp-53 mutant allele. DP16.1͞p53ts cells undergo apoptosis after expression of the wild-type p53 conformation at 32°C. PIDD mRNA is induced by ␥-irradiation in a p53-dependent manner, and the basal level of PIDD mRNA depends on p53 gene status. Overexpression of PIDD also inhibits cell growth in a p53-like manner by inducing apoptosis. Antisense inhibition of PIDD expression was shown to attenuate apoptosis in response to p53 activation and DNA damage, suggesting that PIDD expression is required for p53-dependent death (7).Recently, PIDD was found to be present in a large protein complex containing caspase-2 and the ad...
Triterpenoids are a novel class of compounds being investigated as potential therapeutic agents for the treatment of prostate cancer and other malignancies. Asiatic acid (AA) is a member of the ursane family of triterpenoids and has anticancer activity, but its mechanism of action is not completely understood. To investigate its mechanism of action, PPC-1 prostate cancer cells were treated with AA at increasing concentrations and times. AA induced rapid caspase-dependent and independent cell death that peaked within 8 h of treatment. AA-induced death was associated with early activation of caspases 2, 3, and 8, but not caspase 9. Within 2.5 h of treatment, release of calcium from intracellular stores and dilatation of the endoplasmic reticulum was observed. Thus, disruption of the endoplasmic reticulum and alterations in calcium homeostasis are early events in AA-induced death.
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