Transcriptional Regulation of GI Smooth Muscle in Normal and Diabetic Mice

Abstract

Secondary effects of diabetes can lead to gastroparesis and GI motility dysfunction. Recent studies suggest altered smooth muscle (SM) as well neuronal regulation in these diseases. Consistent with these studies, we found altered expression of smooth muscle contractile proteins in the gut of ob/ob diabetic mice. Utilizing the telokin promoter as a model system, we are elucidating the mechanisms regulating expression of contractile proteins in the gut under normal or diabetic conditions. Telokin is a smooth muscle‐specific protein that is highly expressed in GI SM. Analysis of hprt‐targeted telokin promoter ?‐galactosidase transgenes in vivo, identified a 370bp promoter that is able to mimic expression of endogenous telokin. Within this promoter, a 100bp region is specifically required for telokin expression in GI SM. Analysis of this region revealed evolutionarily conserved binding sites of Sox and SMAD transcription factors. qRT‐PCR analysis demonstrated that Sox4, 5, 6, 7, 12 and 13 are the most abundant Sox proteins in GI SM. Knockdown of Sox7 by siRNA, in GI SM cells, attenuated telokin expression, while knockdown of Sox4, 6 or 12 had no effect. Transduction of GI SMC with dominant negative SMAD4 also attenuated telokin expression. Together these data suggest Sox7 and SMAD proteins are important for regulating expression of contractile proteins in GI SM.Supported by NIH DK 061130, NIH DK 064466‐05