ORIGINAL ARTICLE

Cell Research (2007): 441-448
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Bcl-2 cleavages at two adjacent sites by different caspases promote cisplatin-induced apoptosis

Jianbei Zhu¹, Ying Yang¹ and Jiarui Wu^1,2

Correspondence: Jiarui, Wu Tel: +86 021 54921128; Fax: +86 021 54921011 E-mail: wujr@sibs.ac.cn

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The protein encoded by bcl-2 proto-oncogene plays an important role in the mitochondria-mediated apoptotic pathway. Although the general role of Bcl-2 is anti-apoptotic, previous work showed that Bcl-2 fragments cleaved by caspases could promote apoptotic process. We report herein that Bcl-2 protein was cleaved to produce two fragments of around 23 kDa in human hepatocarcinoma BEL-7404 cells or in Bcl-2 overexpressing CHO cells induced by cisplatin. Treating cells with the general caspase inhibitor z-VAD-fmk blocked the induced cleavage of Bcl-2. Mutagenesis analyses showed that Bcl-2 was cleaved by caspases at two adjacent recognition sites in the loop domain (YEWDD³¹↓AGD³⁴↓V), which could be inhibited by caspase-8 and -3 inhibitors, respectively. Overexpression of the carboxyl terminal 23 kDa fragments increased the sensitivity of CHO cells to cisplatin-induced apoptosis. These results indicate that Bcl-2 can be cleaved into two close fragments by different caspases during cisplatin-induced apoptosis, both of which contribute to the acceleration of apoptotic process.

Cell Research (2007) 17:441–448 doi: 10.1038/cr.2007.36; published online 24 April 2007

Keywords: Bcl-2, apoptosis, cisplatin, caspase-3, caspase-8