Sequential activation of the JNK pathway components,including Rac1/Cdc42,MLKs(mixed-lineage kinases),MKK4/7 and JNKs,plays a required role in many cell death paradigms.Those components are organized by a scaffold prot...Sequential activation of the JNK pathway components,including Rac1/Cdc42,MLKs(mixed-lineage kinases),MKK4/7 and JNKs,plays a required role in many cell death paradigms.Those components are organized by a scaffold protein,POSH(Plenty of SH3’s),to ensure the effective activation of the JNK pathway and cell death upon apoptotic stimuli.We have shown recently that the expression of POSH and MLK family proteins are regulated through protein stability.By generating a variety of mutants,we provide evidence here that the Nterminal half of POSH is accountable for its stability regulation and its over-expression-induced cell death.In addition,POSH’s ability to induce apoptosis is correlated with its stability as well as its MLK binding ability.MLK family’s stability,like that of POSH,requires activation of JNKs.However,we were surprised to find out that the widely used dominant negative(d/n)form of c-Jun could down-regulate MLK’s stability,indicating that peptide from d/n c-Jun can be potentially developed into a therapeutical drug.展开更多
基金supported in part by grants from Ministry of Science and Technology of China,the National Basic Research Program of China(973 Program)(Grant Nos.2007CB947202 and 2006CB500701)the National Programs for High Technology Research and Development Program of China(863 Program)(Grant Nos.2006AA02Z173 and 2009DFA32450)+1 种基金National Natural Science Foundation of China(Grant Nos.30725007,30870527 and 30670663)Chinese Academy of Sciences(Bairen plan and Grant No.KSCX1-YW-R-62/84).
文摘Sequential activation of the JNK pathway components,including Rac1/Cdc42,MLKs(mixed-lineage kinases),MKK4/7 and JNKs,plays a required role in many cell death paradigms.Those components are organized by a scaffold protein,POSH(Plenty of SH3’s),to ensure the effective activation of the JNK pathway and cell death upon apoptotic stimuli.We have shown recently that the expression of POSH and MLK family proteins are regulated through protein stability.By generating a variety of mutants,we provide evidence here that the Nterminal half of POSH is accountable for its stability regulation and its over-expression-induced cell death.In addition,POSH’s ability to induce apoptosis is correlated with its stability as well as its MLK binding ability.MLK family’s stability,like that of POSH,requires activation of JNKs.However,we were surprised to find out that the widely used dominant negative(d/n)form of c-Jun could down-regulate MLK’s stability,indicating that peptide from d/n c-Jun can be potentially developed into a therapeutical drug.
