Synergistic CREB Activation by TORC and CBP

描述(由申请人提供)：胰岛细胞的存活和胰岛素的产生依赖于CREB转录因子的激活，以应对葡萄糖和胰岛素激素水平的升高。由这些信号产生的钙和cAMP第二信使诱导协同靶基因的表达，部分是通过磷酸化依赖的辅助激活因子CBP的招募。此外，TORC共激活子家族的参与对胰岛细胞中CREB的活性起着不可或缺的作用。我们假设CREB需要同时与TORC和CBP相互作用才能完全激活基因。CREB转录输出的强度和CBP招募的程度可能取决于TORC核转位。在建议的时间框架内，我们希望确定CREB：TORC和CREB：CBP复合体对靶基因激活的相对重要性。此外，我们还将确定那些被升高的cAMP和钙协同激活的胰岛基因。最后，我们将探索TORC和CBP之间的物理相互作用，以确定这种联系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是如何通过CREB转化为胰岛细胞内促进细胞存活和胰岛素分泌的遗传程序的。

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.