![]() Subsequently JNKs were shown to phosphorylate and regulate the activity of other AP-1 proteins as well as additional proteins involved in cell proliferation and apoptosis including p53, c-Myc, Bcl-2 and Bim. Initial studies identified JNKs by their ability to phosphorylate the N-terminus of c-Jun, a member of the activating protein 1 (AP-1) transcription factor family. The functions of JNK1 and JNK2 are determined by cell type and by the nature of the stress responsible for their activation. MAPKs and MAPKKs form part of a signal transduction super-family that includes the extracellular signal-regulated kinases (ERKs) and p38 MAPK. In response to stress JNK1 and JNK2 are activated via dual phosphorylation of T183 and Y185 by MAPK kinases (MAPKK), specifically MKK4 and MKK7. The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase family (MAP kinases, MAPKs) and are activated in response to cellular stress. Basal apoptosis was mediated by components of the TNFα response pathway but was mechanistically distinct from TNFα-induced apoptosis. Hypo-phosphorylated c-Jun accumulated to high levels following JNK2 silencing, auto-regulated its own expression and suppressed expression of Bcl-3, an unusual IκB protein and regulator of NFκB. Unexpectedly we discovered that JNK1 and c-Jun promote basal apoptosis in the absence of “activating phosphorylations” typically induced by stress. Silencing JNK2 by RNAi resulted in JNK1-dependent apoptosis of cancer cells via up-regulation of the AP-1 factor c-Jun. This effect was not observed in non-cancer cells. We demonstrate that basal apoptosis is constitutively suppressed by JNK2 in a range of human cancer cell lines. Follow-on, in-depth analyses included exogenous expression of phosphorylation mutants and chromatin immunoprecipitation. Combinatorial RNAi plus gene knockout were employed to access and map basal regulatory pathways of apoptosis. ![]()
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