First Author | Tsui S | Year | 2012 |
Journal | Exp Cell Res | Volume | 318 |
Issue | 8 | Pages | 887-95 |
PubMed ID | 22426149 | Mgi Jnum | J:183388 |
Mgi Id | MGI:5318615 | Doi | 10.1016/j.yexcr.2012.03.001 |
Citation | Tsui S, et al. (2012) CTCF mediates effect of insulin on glucagon expression. Exp Cell Res 318(8):887-95 |
abstractText | Pancreatic islet alpha-cell development and glucagon production are mainly regulated by Pax6 in the homeobox gene families. However, the molecular mechanism fine-tuning the regulation of these events in alpha-cell still remains unclear. In ocular cells, Pax6 transcription is regulated by CTCF through its binding to specific sites in Pax6 promoter. In this study, CTCF-mediated regulations of islet alpha-cell development and glucagon production were investigated in both CTCF transgenic mice and alpha-TC-1-6 cells. Over-expression of CTCF in transgenic mice affected development of pancreatic islets by significantly suppressing alpha-cell population in both embryonic and adult pancreases. The effect of CTCF on Pax6 gene expression and subsequently, on pro-glucagon production was however, examined in pancreatic islet alpha-cells. Over-expression and knock-down of CTCF directly affected Pax6 expression. More importantly, the CTCF binding sites upstream from Pax6 p0 promoter were required for regulating p0 promoter activity in islet alpha-cells. Stimulation of alpha-cells with insulin resulted in a significant increase in CTCF expression and a decrease in Pax6 expression, and consequently suppressed pro-glucagon expression. In contrast, these insulin-induced effects were blocked by knockdown of CTCF mRNA with specific siRNA in alpha-cells. Altogether, our results demonstrated for the first time that CTCF functions as a switch-like molecule between the insulin signaling and the regulations of Pax6 and glucagon expression in pancreatic islet alpha-cells. |