Abstract
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.
Highlights
Apoptosis is an essential cellular program designed to remove unwanted cells from organs and tissues
Loss of SAM and SH3 domain containing 1 (SASH1) is associated with resistance to apoptosis, while overexpression of SASH1 leads to an induction of apoptosis.[7]
We examined the role of SASH1 in the activation of apoptosis in response to ultraviolet light C (UVC) radiation
Summary
Apoptosis is an essential cellular program designed to remove unwanted cells from organs and tissues. Activation of NF-κB occurs when IkB is phosphorylated by the IkB kinase, targeting IkB for proteasome degradation This releases NF-κB, allowing it to translocate to the nucleus.[22] The NF-κB-associated inhibitors of apoptosis c-IAP1 (cellular inhibitor of apoptosis protein-1), c-IAP2 and XIAP (X-linked inhibitor of apoptosis protein) suppress apoptosis through direct inhibition of effector caspases, whereas the members of the B-cell CLL/lymphoma 2 (bcl-2) family activate the proapoptotic members.[23,24,25] Bcl-2 functions within cell survival by controlling the mitochondrial membrane permeability through the inhibition of the proapoptotic factors, BAX (BCL2-associated X protein) and BAK (BCL2 antagonist/ killer 1). We show that following induction of apoptosis, cytoplasmic SASH1 is cleaved by caspase-3 and this cleaved C-terminal fragment of SASH1 is translocated to the nucleus Loss of this site prevents caspase-3 cleavage and results in the loss of nuclear SASH1. NF-κB translocation to the nucleus following the initiation of apoptosis is at least in part dependent on SASH1
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