TY - JOUR T1 - Caspase-8, RIPK1, and RIPK3 Coordinately Regulate Retinoic Acid-Induced Cell Differentiation and Necroptosis JF - bioRxiv DO - 10.1101/156901 SP - 156901 AU - Masataka Someda AU - Shunsuke Kuroki AU - Makoto Tachibana AU - Shin Yonehara Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/06/28/156901.abstract N2 - Caspase-8, which is essential for death receptor-mediated apoptosis, inhibits necroptosis by suppressing the function of RIPK1 and RIPK3 to activate MLKL. We show that knockdown of caspase-8 expression in embryoid bodies derived from ES cells markedly enhances retinoic acid (RA)-induced cell differentiation and necroptosis, both of which are dependent on Ripkl and Ripk3. RA treatment obviously enhanced the expression of RA-specific genes having a retinoic acid response element (RARE) to induce cell differentiation, and induced marked expression of RIPK1, RIPK3 and MLKL to stimulate necroptosis. Caspase-8 knockdown induced RA receptor (RAR) to form a complex with RIPK1 and RIPK3 in the nucleus, and RAR interacting with RIPK1 and RIPK3 showed much stronger binding activity to RARE than RAR without RIPK1 or RIPK3. In Caspase-8-deficient mouse embryos, expression of RA-specific genes was obviously enhanced. Thus, caspase-8, RIPK1, and RIPK3 regulate RA-induced cell differentiation and necroptosis both in vitro and in vivo. ER -