Abstract
Sex-determining region Y-box (SOX) 6 negatively regulates glucose-stimulated insulin secretion from beta-cells and is a down-regulated transcription factor in the pancreatic islet cells of hyperinsulinemic obese mice. To determine the contribution of SOX6 to insulin resistance, we analyzed the effects of SOX6 on cell proliferation. Small interfering RNA-mediated attenuation of SOX6 expression stimulated the proliferation of insulinoma INS-1E and NIH-3T3 cells, whereas retroviral overexpression resulted in inhibition of cell growth. Quantitative real time-PCR analysis revealed that the levels of cyclin D1 transcripts were markedly decreased by SOX6 overexpression. Luciferase-reporter assay with beta-catenin showed that SOX6 suppresses cyclin D1 promoter activities. In vitro binding experiments showed that the LZ/Q domain of SOX6 physically interacts with armadillo repeats 1-4 of beta-catenin. Furthermore, chromatin immunoprecipitation assay revealed that increased SOX6 expression significantly reduced the levels of acetylated histones H3 and H4 at the cyclin D1 promoter. By using a histone deacetylase (HDAC) inhibitor and co-immunoprecipitation analysis, we showed that SOX6 suppressed cyclin D1 activities by interacting withbeta-catenin and HDAC1. The data presented suggest that SOX6 may be an important factor in obesity-related insulin resistance.
Highlights
In obesity-related insulin resistance, pancreatic islets compensate for chronic insulin insensitivity by expanding -cell mass and increasing insulin secretory capacity [1, 2]
To further define the role of SOX6 in obesity-related insulin resistance, we analyzed the effects of SOX6 expression on cell proliferation. small interfering RNA (siRNA)-mediated knockdown of SOX6 significantly stimulated cell proliferation, whereas induced SOX6 expression resulted in the inhibition of cell growth
Proliferation—In a previous study, we showed that SOX6 expression is down-regulated in hyperinsulinemic obese mice and that this attenuation led to increased insulin secretion from cultured -cells [3]
Summary
In obesity-related insulin resistance, pancreatic islets compensate for chronic insulin insensitivity by expanding -cell mass and increasing insulin secretory capacity [1, 2]. A series of deletion mutants of -catenin was translated in fected with SOX6 were ϳ30% of those in the cells transfected vitro with [35S]methionine and incubated with GST-fused SOX6 with GFP, whereas those of other cell cycle-regulating proteins, or GST alone, and the resulting complexes were precipitated with including cyclins A2, D2, D3, and E1, were decreased by ϳ50% glutathione beads as described under “Experimental Proce-
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