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首页> 外文期刊>Cell death & disease. >Activation and cleavage of SASH1 by caspase-3 mediates an apoptotic response
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Activation and cleavage of SASH1 by caspase-3 mediates an apoptotic response

机译：caspase-3对SASH1的激活和切割介导凋亡反应。

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摘要

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- κ B (NF- κ B) to the nucleus. The use of the NF- κ B inhibitor DHMEQ demonstrated that the effect of SASH1 on apoptosis was dependent on NF- κ B, indicating a codependence between SASH1 and NF- κ B for this process.
机译：凋亡是高度调控的细胞过程，其功能是从多细胞生物中去除不需要的细胞。该途径通常在癌症中被破坏，从而为肿瘤提供避免细胞死亡并促进生长和存活的机制。推定的肿瘤抑制因子SASH1（含有SAM和SH3结构域的蛋白1）先前与细胞凋亡的调控有关;但是，尚不清楚SASH1在此过程中的分子作用。在这项研究中，我们证明SASH1被UVC诱导的凋亡后的caspase-3裂解。 SASH1的蛋白水解使C端片段从细胞质转移到细胞核，并与染色质结合。野生型SASH1的过表达或代表氨基酸231–1247的SASH1的切割形式导致细胞凋亡增加。相反，SASH1切割位点的突变抑制了核易位并阻止了细胞凋亡的启动。 SASH1裂解也是转录因子核因子κB（NF-κB）有效转移到细胞核中所必需的。 NF-κB抑制剂DHMEQ的使用证明SASH1对细胞凋亡的作用依赖于NF-κB，表明该过程中SASH1和NF-κB相互依赖。

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