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Publication : Combination of IAP antagonist and IFNγ activates novel caspase-10- and RIPK1-dependent cell death pathways.

First Author  Tanzer MC Year  2017
Journal  Cell Death Differ Volume  24
Issue  3 Pages  481-491
PubMed ID  28106882 Mgi Jnum  J:259265
Mgi Id  MGI:6140724 Doi  10.1038/cdd.2016.147
Citation  Tanzer MC, et al. (2017) Combination of IAP antagonist and IFNgamma activates novel caspase-10- and RIPK1-dependent cell death pathways. Cell Death Differ 24(3):481-491
abstractText  Peptido-mimetic inhibitor of apoptosis protein (IAP) antagonists (Smac mimetics (SMs)) can kill tumour cells by depleting endogenous IAPs and thereby inducing tumour necrosis factor (TNF) production. We found that interferon-gamma (IFNgamma) synergises with SMs to kill cancer cells independently of TNF- and other cell death receptor signalling pathways. Surprisingly, CRISPR/Cas9 HT29 cells doubly deficient for caspase-8 and the necroptotic pathway mediators RIPK3 or MLKL were still sensitive to IFNgamma/SM-induced killing. Triple CRISPR/Cas9-knockout HT29 cells lacking caspase-10 in addition to caspase-8 and RIPK3 or MLKL were resistant to IFNgamma/SM killing. Caspase-8 and RIPK1 deficiency was, however, sufficient to protect cells from IFNgamma/SM-induced cell death, implying a role for RIPK1 in the activation of caspase-10. These data show that RIPK1 and caspase-10 mediate cell death in HT29 cells when caspase-8-mediated apoptosis and necroptosis are blocked and help to clarify how SMs operate as chemotherapeutic agents.
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