Activation and cleavage of SASH1 by caspase-3 mediates an apoptotic response.
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.
Cancer and Ageing Program, Institute of Health and Biomedical Innovation at the Translational Research Institute (TRI), Queensland University of Technology (QUT) and Princess Alexandra Hospital, Level 6, Translational Research Institute, Brisbane, QLD, Australia.
Joshua T
JT
Burgess
Cancer and Ageing Program, Institute of Health and Biomedical Innovation at the Translational Research Institute (TRI), Queensland University of Technology (QUT) and Princess Alexandra Hospital, Level 6, Translational Research Institute, Brisbane, QLD, Australia.|Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, QLD 4102, Australia.
Emma
E
Bolderson
Cancer and Ageing Program, Institute of Health and Biomedical Innovation at the Translational Research Institute (TRI), Queensland University of Technology (QUT) and Princess Alexandra Hospital, Level 6, Translational Research Institute, Brisbane, QLD, Australia.
Mark N
MN
Adams
Cancer and Ageing Program, Institute of Health and Biomedical Innovation at the Translational Research Institute (TRI), Queensland University of Technology (QUT) and Princess Alexandra Hospital, Level 6, Translational Research Institute, Brisbane, QLD, Australia.
Anne-Marie
AM
Baird
Northern Ireland Centre for Stratified Medicine, University of Ulster, C-TRIC Building, Altnagelvin Hospital Campus, Glenshane Road, Londonderry BT47 6SB, UK.|Center for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.
Shu-Dong
SD
Zhang
Thoracic Oncology Research Group, Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Republic of Ireland.
Kathy A
KA
Gately
Department of Molecular Target Medicine Screening, Aichi Medical University, Nagakute, Japan.
Kazuo
K
Umezawa
Cancer and Ageing Program, Institute of Health and Biomedical Innovation at the Translational Research Institute (TRI), Queensland University of Technology (QUT) and Princess Alexandra Hospital, Level 6, Translational Research Institute, Brisbane, QLD, Australia.|Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, QLD 4102, Australia.
Kenneth J
KJ
O'Byrne
Cancer and Ageing Program, Institute of Health and Biomedical Innovation at the Translational Research Institute (TRI), Queensland University of Technology (QUT) and Princess Alexandra Hospital, Level 6, Translational Research Institute, Brisbane, QLD, Australia.|Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, QLD 4102, Australia.
Derek J
DJ
Richard
D000072283:A549 Cells; D017209:Apoptosis; D001224:Aspartic Acid / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D055550:Protein Stability; D021381:Protein Transport; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D016328:NF-kappa B; C474743:SASH1 protein, human; D025521:Tumor Suppressor Proteins; D001224:Aspartic Acid; D053148:Caspase 3