Glucose and incretin hormones trigger the expression of genetic programs that enhance islet cell survival and promote insulin release during feeding. The activation of cAMP and calcium pathways in response to these cues promotes islet gene expression and beta cell survival in part by stimulating the phosphorylation of CREB at Ser133, a modification that stimulates recruitment of the coactivator paralogs CBP and P300 to the promoter. Mice with knockin mutations in CBP and P300 that disrupt their association with CREB show only modest changes in cAMP dependent transcription, however, suggesting the potential involvement of additional CREB coactivators in this process. The current proposal focuses on the role of a novel family of CREB coactivators, designated TORCs for Transducers of Regulated CREB activity, in promoting islet gene expression. Preliminary studies reveal that islet TORC proteins are retained in the cytoplasm under basal conditions, migrating to the nucleus in response to cAMP and calcium signals where they potentiate CREB target gene expression.
Specific Aim I addresses the mechanism by which TORC activity is suppressed under basal conditions, focusing on the role of a TORC associated protein kinase in promoting TORC phosphorylation and cytoplasmic retention via an interaction with 14-3-3 proteins.
Aim II addresses the mechanism of TORC activation in response to cAMP and calcium, with particular emphasis on the role of the ser/thr phosphatase calcineurin in dephosphorylating and promoting nuclear entry of TORC.
Aim III examines the relative importance of CREB:TORC and CREB:CBP complexes for pancreatic islet gene expression by using mutant CREB polypeptides that are defective in either CBP or TORC interaction. Regulatory contributions of TORC and CBP/P300 towards CREB target gene expression islet cells will also be explored by disrupting the expression of each coactivator through RNAi mediated knockdown. Finally, the role of TORCs in pancreatic islet function will be determined by generating mice with a conditional knockout of the TORC genes. Post-transplant diabetes is a frequent complication in patients receiving calcineurin inhibitors such as FK506 for immunosuppression. The proposed studies will reveal whether these inhibitors promote islet cell death, in part by interfering with expression of islet survival genes through the CREB:TORC pathway.
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