TIFA,also called T2BP,was first identified using yeast two-hybrid screening.Our previous work showed that TIFA suppresses hepatocellular carcinoma(HCC)progression via apoptosis and cell cycle arrest.However,the mechan...TIFA,also called T2BP,was first identified using yeast two-hybrid screening.Our previous work showed that TIFA suppresses hepatocellular carcinoma(HCC)progression via apoptosis and cell cycle arrest.However,the mechanism by which this TIFA suppression occurs remains unclear.Here we demonstrated that TIFA-induced apoptosis demonstrates two distinct time patterns(i.e.,at 48 h and 47 days)when TIFA reconstitution occurs.Moreover,we found that MALT1(a competitor of TIFA)plays a crucial role in short-duration TIFA reconstitution.In this regard,MALT1 silencing with shRNA markedly enhances TIFA-induced apoptosis in vitro and in vivo.In addition,TIFA overexpression triggers JNK and p38 activation in long-duration TIFA reconstitution through TRAF6 binding.In particular,JNK activation leads to TIFA-induced apoptosis while p38 activation governs TIFA-induced cell cycle arrest by p53-p21 signaling in vitro and in vivo.Our data suggest a novel mechanism by which TIFA suppresses HCC progression via both MALT1-dependent and MALT1-independent signaling pathways.This may provide insights into a novel targets where HCC progression may be vulnerable to clinical treatment.展开更多
基金This project is supported by the National Basic Research Program(973)of China(No.2013CB967202)the National Natural Science Foundation of China(No.81273331)+2 种基金the National Natural Science Foundation of China(No.81470354)National Natural Science Foundation of China(81301856NL).
文摘TIFA,also called T2BP,was first identified using yeast two-hybrid screening.Our previous work showed that TIFA suppresses hepatocellular carcinoma(HCC)progression via apoptosis and cell cycle arrest.However,the mechanism by which this TIFA suppression occurs remains unclear.Here we demonstrated that TIFA-induced apoptosis demonstrates two distinct time patterns(i.e.,at 48 h and 47 days)when TIFA reconstitution occurs.Moreover,we found that MALT1(a competitor of TIFA)plays a crucial role in short-duration TIFA reconstitution.In this regard,MALT1 silencing with shRNA markedly enhances TIFA-induced apoptosis in vitro and in vivo.In addition,TIFA overexpression triggers JNK and p38 activation in long-duration TIFA reconstitution through TRAF6 binding.In particular,JNK activation leads to TIFA-induced apoptosis while p38 activation governs TIFA-induced cell cycle arrest by p53-p21 signaling in vitro and in vivo.Our data suggest a novel mechanism by which TIFA suppresses HCC progression via both MALT1-dependent and MALT1-independent signaling pathways.This may provide insights into a novel targets where HCC progression may be vulnerable to clinical treatment.
