TORC-dependent CREB activity is regulated by glucose in beta cells

Abstract

Our bodies go through cycles of feeding and fasting, and in order to control blood glucose levels, will respond by releasing hormones such as glucagon and insulin. After feeding, insulin is released from the pancreatic beta cells to reduce blood glucose levels. When our bodies are unable to do this the result is hyperglycemia, leading to diabetes, of which there are two types. Type 1 diabetes is an autoimmune disease where the body's T cells attack and destroy the insulin producing beta cells, rendering these patients insulindependent. Type 2 diabetes however, results from chronic high blood glucose levels. This will lead to insulin resistance and eventually beta cell apoptosis. Recently it was observed that the transcription factor cAMP Response Element Binding (CREB) protein is required for beta cell survival. Expression of a dominantnegative CREB under the control of the beta cell specific rat insulin promoter leads to progressive reduction of beta cell mass and diabetes in mice. Interestingly, the same signals that lead to insulin secretion, cAMP and Ca, are required for activation of CREB. Transducers of Regulated CREB activity (TORCs) were recently identified as CREB coactivators that are responsible for the synergistic activation of CREB target genes by cAMP and Ca. Under resting conditions phosphorylated TORCs are sequestered in the cytoplasm by 14-3-3 proteins. After stimulation with cAMP and Ca TORCs become dephosphorylated and enter the nucleus, where they bind to the bZIP domain of CREB to activate transcription. In the absence of these stimuli, TORC2 is phosphorylated by the salt inducible kinase 2 (SIK2) at S171. Treatment of 293 cells with cAMP leads to the phosphorylation of SIK2 and therefore the dissociation of this