We and others have reported the isolation of a clone encoding for the CCAAT/Enhancer Binding Protein (C/EBP)(, and we have established that C/EBP( is a critical modulator of both gene expression and the G1/S phase transition of the cell cycle. Activation of ribosomal S6-kinase (RSK)- 2 and phosphorylation of C/EBP( on its activation domain plays a major role in cell survival, at least in part, by binding to the procaspase 8 complex and preventing its self-cleavage and activation. Our recent discovery identifies a novel non-transcriptional role of C/EBP( acting as an inhibitor of the caspase 8 pathway. It remains to be determined what are the mechanisms involved, and whether this inhibition is direct and/or indirect. We have determined that the MAPK-RSK-C/EBP( signaling cascade modulates expression of FLIPL, a critical inhibitor of procaspase 8. Also, we have found that C/EBP( associates with FLIPL and that this association is down-regulated by FAS signaling. As expected, the non-phosphorylatable C/EBP(Ala217 mutant prevents stellate cell activation induced by the collagen type I matrix or growth factor/MAPK/RSK signaling cascade, while the phosphorylation mimic C/EBP(Glu217 mutant blocks stellate cell apoptosis initiated by death receptors or proteasome inhibitors (caspase 8 pathway). This proposal will study the mechanism(s) by which C/EBP( modulates the extrinsic apoptotic pathway in hepatic stellate cells.
The specific aims of this proposal are to assess: 1. The regulation of FLIPL activity by MAPK-RSK-C/EBP( signaling in stellate cells. 2. The role of C/EBP( phosphorylation on stellate cell survival. 3. The modulation of stellate cell survival in C/EBP(Glu217 transgenic mice.
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