S Tsui1, W Dai, L Lu. 1. Department of Medicine, David Geffen School of Medicine University of California Los Angeles, Torrance, CA, 90502, USA.
Abstract
OBJECTIVES: Pancreatic islet β-cell survival is paramount for regulation of insulin activity and for maintaining glucose homeostasis. Recently, Pax6 has been shown to be essential for many vital functions in β-cells, although many molecular mechanisms of its homeostasis in β-cells remain unclear. The present study investigates novel effects of glucose- and insulin-induced CCCTC-binding factor (CTCF) activity on Pax6 gene expression as well as for subsequent effects of insulin-activated signalling pathways, on β-cell proliferation. MATERIALS AND METHODS: Pancreatic β-TC-1-6 cells were cultured in DMEM and stimulated with high concentrations of glucose (5-125 mm); cell viability was assessed by MTT assay. Effects of CTCF on Pax6 were evaluated in the high glucose-induced environment and CTCF/Erk-suppressed cells, by promoter reporter and western blotting analyses. RESULTS: Increases in glucose and insulin concentrations upregulated CTCF and consequently downregulated Pax6 in β-cell survival and proliferation. Knocking-down CTCF directly affected Pax6 transcription through CTCF binding and blocked the response to glucose. Altered Erk activity mediated effects of CTCF on controlling Pax6 expression, which partially regulated β-cell proliferation. CONCLUSIONS: CTCF functioned as a molecular mediator between insulin-induced upstream Erk signalling and Pax6 expression in these pancreatic β-cells. This pathway may contribute to regulation of β-cell survival and proliferation.
OBJECTIVES:Pancreatic islet β-cell survival is paramount for regulation of insulin activity and for maintaining glucose homeostasis. Recently, Pax6 has been shown to be essential for many vital functions in β-cells, although many molecular mechanisms of its homeostasis in β-cells remain unclear. The present study investigates novel effects of glucose- and insulin-induced CCCTC-binding factor (CTCF) activity on Pax6 gene expression as well as for subsequent effects of insulin-activated signalling pathways, on β-cell proliferation. MATERIALS AND METHODS:Pancreatic β-TC-1-6 cells were cultured in DMEM and stimulated with high concentrations of glucose (5-125 mm); cell viability was assessed by MTT assay. Effects of CTCF on Pax6 were evaluated in the high glucose-induced environment and CTCF/Erk-suppressed cells, by promoter reporter and western blotting analyses. RESULTS: Increases in glucose and insulin concentrations upregulated CTCF and consequently downregulated Pax6 in β-cell survival and proliferation. Knocking-down CTCF directly affected Pax6 transcription through CTCF binding and blocked the response to glucose. Altered Erk activity mediated effects of CTCF on controlling Pax6expression, which partially regulated β-cell proliferation. CONCLUSIONS:CTCF functioned as a molecular mediator between insulin-induced upstream Erk signalling and Pax6expression in these pancreatic β-cells. This pathway may contribute to regulation of β-cell survival and proliferation.
Authors: M Blandino-Rosano; E U Alejandro; A Sathyamurthy; J O Scheys; B Gregg; A Y Chen; L Rachdi; A Weiss; D J Barker; A P Gould; L Elghazi; E Bernal-Mizrachi Journal: Diabetologia Date: 2012-02-12 Impact factor: 10.122
Authors: H Nakagawa; R B Chadwick; P Peltomaki; C Plass; Y Nakamura; A de La Chapelle Journal: Proc Natl Acad Sci U S A Date: 2000-12-19 Impact factor: 11.205