Synergistic CREB Activation by TORC and CBP

描述（由申请方提供）：胰岛细胞存活和胰岛素产生依赖于CREB转录因子的激活，以响应葡萄糖和肠促胰岛素激素水平升高。通过这些信号产生钙和cAMP第二信使诱导协同靶基因表达，部分是通过共激活因子CBP的磷酸化依赖性募集。此外，TORC家族的辅激活因子的参与对胰岛细胞中的CREB活性起着不可或缺的作用。我们假设CREB需要同时与TORC和CBP相互作用以实现完整的基因激活。CREB转录输出的强度和CBP募集的程度可能取决于TORC核转位。在建议的时间范围内，我们希望确定CREB：TORC和CREB：CBP复合物对靶基因激活的相对重要性。此外，我们将确定那些胰岛基因的协同激活升高cAMP和钙。最后，我们将探讨TORC和CBP之间的物理相互作用，以确定这种关联如何影响每个蛋白质的转录活性。这项工作将有助于阐明激素信号如何通过CREB转化为胰岛细胞内的遗传程序，促进细胞存活和胰岛素分泌。

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.