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抗癌剤誘導のアポトーシスにおけるp21^waf1/Cip1の切断とその役割：張永克¹、藤田直也¹ 、鶴尾隆^1,2（¹東大・分生研，²癌研・癌化療セ）

Caspase-mediated cleavage of p21^Waf1/Cip1 converts cells from growth arrest to apoptosis : Yongke ZHANG¹, Naoya FUJITA¹, Takashi TSURUO^1,2 (¹Inst. Mol. Cell. Biosci. Univ. Tokyo, 2Cancer Chemother. Ctr., Jpn. Fdn. Cancer Res.)

The caspase family of cysteine-containing aspartate-specific proteases have been implicated as critical mediators of apoptosis through cleavage of its substrates. Here we reported that the cyclin-dependent kinase inhibitor p21^Waf1/Cip1, a downstream effector of p53-dependent cell growth arrest, was cleaved specifically by caspase-3 (CPP32) during DNA damage-induced apoptosis. The cleavage occurred after the (109)DHVD(112) sequence, removing the C-terminal 52 amino acids. After cleavage, p21 failed to bind to the proliferating cell nuclear antigen (PCNA), which is involved in DNA replication and repair. Moreover, lacking the nuclear localization signal (NLS) sequence by removal the C-terminal domain, the cleaved p21 lost the capability to localize in the nucleus. Furthermore, we demonstrated that cleavage of p21 led the cells to be released from G1 arrest and abolished the inhibitory effect of p21 on apoptosis. These results indicate that caspase-3-mediated proteolytic inactivation of p21 may convert cells from growth arrest to apoptosis. Thus, therapies aimed at activating caspase-3, together with chemotherapeutic agents, would overcome the apoptosis-inhibiting function of p21 and increase the susceptibility of growth-arrested cancer cells to chemotherapy.