Goldstein Ido, Hager Gordon L
Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Endocrinology. 2018 Jan 1;159(1):206-216. doi: 10.1210/en.2017-00521.
Upon lowered blood glucose occurring during fasting, glucagon is secreted from pancreatic islets, exerting various metabolic effects to normalize glucose levels. A considerable portion of these effects is mediated by glucagon-activated transcription factors (TFs) in liver. Glucagon directly activates several TFs via immediate cyclic adenosine monophosphate (cAMP)- and calcium-dependent signaling events. Among these TFs, cAMP response element-binding protein (CREB) is a major factor. CREB recruits histone-modifying enzymes and cooperates with other TFs on the chromatin template to increase the rate of gene transcription. In addition to direct signal transduction, the transcriptional effects of glucagon are also influenced by dynamic TF cross talk. Specifically, assisted loading of one TF by a companion TF leads to increased binding and activity. Lastly, transcriptional regulation by glucagon is also exerted by TF cascades by which a primary TF induces the gene expression of secondary TFs that bring about their activity a few hours after the initial glucagon signal. This mechanism of a delayed response may be instrumental in establishing the temporal organization of the fasting response by which distinct metabolic events separate early from prolonged fasting. In this mini-review, we summarize recent advances and critical discoveries in glucagon-dependent gene regulation with a focus on direct TF activation, dynamic TF cross talk, and TF cascades.
在空腹期间血糖水平降低时，胰高血糖素从胰岛分泌出来，发挥各种代谢作用以使血糖水平恢复正常。这些作用的很大一部分是由肝脏中胰高血糖素激活的转录因子（TFs）介导的。胰高血糖素通过直接的环磷酸腺苷（cAMP）和钙依赖性信号转导事件直接激活几种转录因子。在这些转录因子中，cAMP反应元件结合蛋白（CREB）是主要因素。CREB招募组蛋白修饰酶，并在染色质模板上与其他转录因子协同作用，以提高基因转录速率。除了直接信号转导外，胰高血糖素的转录作用还受到动态转录因子相互作用的影响。具体而言，一个转录因子由另一个伴随转录因子协助加载会导致结合增加和活性增强。最后，胰高血糖素的转录调控也通过转录因子级联发挥作用，即初级转录因子诱导次级转录因子的基因表达，这些次级转录因子在最初的胰高血糖素信号发出数小时后发挥其活性。这种延迟反应机制可能有助于建立禁食反应的时间组织，通过这种组织，不同的代谢事件在早期与长期禁食区分开来。在本综述中，我们总结了胰高血糖素依赖性基因调控的最新进展和关键发现，重点关注直接转录因子激活、动态转录因子相互作用和转录因子级联。
