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Supplementary Figure 1 from p21 Blocks Irradiation-Induced Apoptosis Downstream of Mitochondria by Inhibition of Cyclin-Dependent Kinase–Mediated Caspase-9 Activation

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posted on 2023-03-30, 17:03 authored by Dennis Sohn, Frank Essmann, Klaus Schulze-Osthoff, Reiner U. Jänicke
Supplementary Figure 1 from p21 Blocks Irradiation-Induced Apoptosis Downstream of Mitochondria by Inhibition of Cyclin-Dependent Kinase–Mediated Caspase-9 Activation

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ARTICLE ABSTRACT

The role of the cyclin-dependent kinase (CDK) inhibitor p21 as a mediator of p53-induced growth arrest is well established. In addition, recent data provide strong evidence for new emerging functions of p21, including a role as a modulator of apoptosis. The mechanisms, however, by which p21 interferes with the death machinery, especially following ionizing radiation (IR), are largely unknown. Here, we report that IR induced caspase-9 and caspase-3 activation and subsequent apoptosis only in p21-deficient colon carcinoma cells, whereas similar treated wild-type cells were permanently arrested in the G2-M phase, correlating with the induction of cellular senescence. Interestingly, activation of the mitochondrial pathway, including caspase-2 processing, depolarization of the outer mitochondrial membrane, and cytochrome c release, was achieved by IR in both cell lines, indicating that p21 inhibits an event downstream of mitochondria but preceding caspase-9 activation. IR-induced p21 protein expression was restricted to the nucleus, and no evidence for a mitochondrial or cytoplasmic association was found. In addition, p21 did neither interact with caspase-3 or caspase-9, suggesting that these events are not required for the observed protection. Consistent with this assumption, we found that CDK inhibitors potently abrogated IR-induced caspase processing and activation without affecting mitochondrial events. In addition, in vitro caspase activation assays yielded higher caspase-3 activities in extracts of irradiated p21-deficient cells compared with extracts of similar treated wild-type cells. Thus, our results strongly indicate that p21 protects cells from IR-induced apoptosis by suppression of CDK activity that seems to be required for activation of the caspase cascade downstream of the mitochondria. (Cancer Res 2006; 66(23): 11254-62)

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