Serum response factor cleavage by caspases 3 and 7 linked to apoptosis in human BJAB cells
Serum response factor cleavage by caspases 3 and 7 linked to apoptosis in human BJAB cells
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DOI：
10.1074/jbc.m103877200
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发表时间：
2001-09-07
影响因子：
4.8
通讯作者：
Shaw, PE
中科院分区：
文献类型：
--
作者：
Drewett, V;Devitt, A;Shaw, PE
凋亡涉及细胞过程的停止、细胞内细胞器的破坏，以及最终凋亡细胞从体内的非炎性清除。对于这些事件重要的是蛋白酶家族，半胱天冬酶，其被蛋白水解切割级联激活并通过靶向细胞内的关键蛋白来驱动凋亡。在这里，我们证明了血清反应因子（SRF），增殖基因表达所必需的转录因子，被半胱天冬酶切割，这种切割发生在增殖的小鼠成纤维细胞，并可以在人类B细胞系BJAB诱导。我们鉴定了SRF切割发生的两个主要位点为Asp（245）和Asp（254），它们是负责切割的半胱天冬酶，并在BJAB细胞中产生了抗切割的SRF突变体。SRF切割的生理和功能意义的调查表明，它与e-fos表达的损失，从而既不SRF切割片段保留转录活性。此外，BJAB细胞中不可切割的SRF的表达抑制Fas交联诱导的细胞凋亡。这些结果表明，细胞凋亡的进行，促进细胞存活和增殖的转录事件，其中SRF参与，必须首先被灭活。
Apoptosis involves the cessation of cellular processes, the breakdown of intracellular organelles, and, finally, the nonphlogistic clearance of apoptotic cells from the body. Important for these events is a family of proteases, caspases, which are activated by a proteolytic cleavage cascade and drive apoptosis by targeting key proteins within the cell. Here, we demonstrate that serum response factor (SRF), a transcription factor essential for proliferative gene expression, is cleaved by caspases and that this cleavage occurs in proliferating murine fibroblasts and can be induced in the human B-cell line BJAB. We identify the two major sites at which SRF cleavage occurs as Asp(245) and Asp(254), the caspases responsible for the cleavage and generate a mutant of SRF resistant to cleavage in BJAB cells. Investigation of the physiological and functional significance of SRF cleavage reveals that it correlates with the loss of e-fos expression, whereby neither SRF cleavage fragment retains transcriptional activity. Moreover, the expression of a noncleavable SRF in BJAB cells suppresses apoptosis induced by Fas cross-linking. These results suggest that for apoptosis to proceed, the transcriptional events promoting cell survival and proliferation, in which SRF is involved, must first be inactivated.