Synergistic CREB Activation by TORC and CBP

Salk Institute For Biological Studies, La Jolla CA

Investigators

Abstract

DESCRIPTION (provided by applicant): Islet cell survival and insulin production depend upon activation of the CREB transcription factor in response to elevated levels of glucose and incretin hormones. Production of calcium and cAMP second messengers by these cues induces synergistic target gene expression in part by phosphorylation dependent recruitment of the coactivator CBP. Additionally, engagement of the TORC family of coactivators plays an indispensable role for CREB activity in islet cells. We hypothesize that CREB requires simultaneous interaction with both TORC and CBP for full gene activation. The strength of CREB transcriptional output and the degree of CBP recruitment likely depends upon TORC nuclear translocation. Within the proposed timeframe we expect to determine the relative importance of CREB: TORC and CREB:CBP complexes for target gene activation. In addition we will identify those islet genes that are coordinately activated by elevated cAMP and calcium. Lastly we will explore the physical interaction between TORC and CBP to determine how this association effects the transcriptional activity of each protein. This work will help to elucidate how hormonal cues are translated via CREB into a genetic program within islet cells that promotes cell survival and insulin secretion.