Activation and cleavage of SASH1 by caspase-3 mediates an apoptotic response.
Activation and cleavage of SASH1 by caspase-3 mediates an apoptotic response.
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caspase-3对SASH1的激活和切割介导了凋亡反应。
DOI：
10.1038/cddis.2016.364
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发表时间：
2016-11-10
影响因子：
9
通讯作者：
Richard DJ
中科院分区：
文献类型：
--
作者：
Burgess JT;Bolderson E;Adams MN;Baird AM;Zhang SD;Gately KA;Umezawa K;O'Byrne KJ;Richard DJ
细胞凋亡是一种高度调节的细胞过程，其功能是从多细胞生物体中去除不需要的细胞。这种途径在癌症中经常被破坏，为肿瘤提供了避免细胞死亡并促进生长和存活的机制。假定的肿瘤抑制因子SASH 1（SAM和SH 3结构域包含蛋白1），先前已涉及细胞凋亡的调节;然而，SASH 1在此过程中的分子作用仍不清楚。在这项研究中，我们证明SASH 1被切割的caspase-3后，紫外线诱导的细胞凋亡。SASH 1的蛋白水解使C-末端片段从细胞质易位到细胞核，在那里它与染色质结合。野生型SASH 1或代表氨基酸231-1247的SASH 1的切割形式的过表达导致细胞凋亡的增加。相反，SASH 1切割位点的突变抑制核转位并阻止细胞凋亡的启动。SASH 1裂解也是转录因子核因子-κB（NF-κB）有效转运至细胞核所必需的。NF-κB抑制剂DHMEQ的使用表明SASH 1对凋亡的作用依赖于NF-κB，表明SASH 1和NF-κB在该过程中相互依赖。
Apoptosis is a highly regulated cellular process that functions to remove undesired cells from multicellular organisms. This pathway is often disrupted in cancer, providing tumours with a mechanism to avoid cell death and promote growth and survival. The putative tumour suppressor, SASH1 (SAM and SH3 domain containing protein 1), has been previously implicated in the regulation of apoptosis; however, the molecular role of SASH1 in this process is still unclear. In this study, we demonstrate that SASH1 is cleaved by caspase-3 following UVC-induced apoptosis. Proteolysis of SASH1 enables the C-terminal fragment to translocate from the cytoplasm to the nucleus where it associates with chromatin. The overexpression of wild-type SASH1 or a cleaved form of SASH1 representing amino acids 231–1247 leads to an increase in apoptosis. Conversely, mutation of the SASH1 cleavage site inhibits nuclear translocation and prevents the initiation of apoptosis. SASH1 cleavage is also required for the efficient translocation of the transcription factor nuclear factor-κB (NF-κB) to the nucleus. The use of the NF-κB inhibitor DHMEQ demonstrated that the effect of SASH1 on apoptosis was dependent on NF-κB, indicating a codependence between SASH1 and NF-κB for this process.