Abstract
AbstractAmong caspase family members, Caspase-8 is unique, with associated critical activities to induce and suppress death receptor-mediated apoptosis and necroptosis, respectively. Caspase-8 inhibits necroptosis by suppressing the function of receptor-interacting protein kinase 1 (RIPK1 or RIP1) and RIPK3 to activate mixed lineage kinase domain-like (MLKL). Disruption ofCaspase-8expression causes embryonic lethality in mice, which is rescued by depletion of eitherRipk3orMlkl, indicating that the embryonic lethality is caused by activation of necroptosis. Here, we show that knockdown ofCaspase-8expression in embryoid bodies derived from ES cells markedly enhances retinoic acid (RA)-induced cell differentiation and necroptosis, both of which are dependent onRipk1andRipk3; however, the enhancement of RA-induced cell differentiation is independent ofMlkland necrosome formation. RA treatment obviously enhanced the expression of RA-specific target genes having the retinoic acid response element (RARE) in their promoter regions to induce cell differentiation, and induced marked expression of RIPK1, RIPK3, and MLKL to stimulate necroptosis.Caspase-8knockdown induced RIPK1 and RIPK3 to translocate into the nucleus and to form a complex with RA receptor (RAR), and RAR interacting with RIPK1 and RIPK3 showed much stronger binding activity toRAREthan RAR without RIPK1 or RIPK3. InCaspase-8-deficient as well asCaspase-8- andMlkl-deficient mouse embryos, the expression of RA-specific target genes was obviously enhanced. Thus, Caspase-8, RIPK1, and RIPK3 regulate RA-induced cell differentiation and necroptosis both in vitro and in vivo.
Funder
Ministry of Education, Culture, Sports, Science and Technology
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Molecular Biology
Cited by
25 articles.
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