Almost 12 million Americans suffer from insulin dependent diabetes mellitus (IDDM), and the attendant hyperglycemia in these patients appears to account for a majority of microvascular and neurologic complications. To eliminate the need for constant glucose monitoring in diabetic patients, a number of cellular replacement strategies have been proposed. But such approaches will ultimately require a basic understanding of the mechanism by which insulin gene expression is regulated both constitutively and in response to glucose. Within the insulin promoter, two AT rich motifs termed FLAT and P appear to be critical for high level expression of the insulin gene in beta islet cell lines. We have recently characterized a novel pancreatic homeobox factor, referred to as STF-1, which binds to the FLAT and P elements and which stimulates insulin promoter activity in heterologous cells. In this proposal we will test whether STF-1 is a principal regulator of insulin gene expression in pancreatic beta cells. I. To test whether STF-1 is indeed critical for insulin gene expression, we will inhibit STF-1 activity by microinjection of STF-1 antisera into beta islet cells and by immunodepletion of in vitro transcription extracts. We will further test this hypothesis by expressing anti-sense STF-1 RNA in stably transfected beta islet cell lines. II. Recent evidence suggesting that STF-1 can stimulate insulin gene expression in heterologous cells by cooperating with the basic helix loop helix factor E47 has prompted us to test the mechanism by which these two proteins interact to stimulate high level expression of the insulin gene. III. Like other tissue-specific regulators, STF- 1 is expressed primarily in pancreatic islet cells, and we will analyze the STF-1 promoter to identify cis-acting elements and cognate factors which target STF-1 expression to these cells. Based on recent evidence that STF-1 mRNA accumulation is rapidly inhibited by glucocorticoids, we will further examine whether dexamethasone interferes with STF-1 promoter activity and thereby inhibits insulin gene expression. A number of patients receiving chronic glucocorticoid therapy (i.e. rheumatoid arthritis) often develop symptoms of insulin deficiency, and our studies may identify STF-1 as an important target for glucocorticoid action in the pancreas.
| Tsai, Wen-Wei; Matsumura, Shigenobu; Liu, Weiyi et al. (2015) ATF3 mediates inhibitory effects of ethanol on hepatic gluconeogenesis. Proc Natl Acad Sci U S A 112:2699-704 |
| Hernandez, Jeniffer B; Chang, Christina; LeBlanc, Mathias et al. (2015) The CREB/CRTC2 pathway modulates autoimmune disease by promoting Th17 differentiation. Nat Commun 6:7216 |
| Blanchet, Emilie; Van de Velde, Sam; Matsumura, Shigenobu et al. (2015) Feedback inhibition of CREB signaling promotes beta cell dysfunction in insulin resistance. Cell Rep 10:1149-57 |
| Paz, Jose C; Park, Sangho; Phillips, Naomi et al. (2014) Combinatorial regulation of a signal-dependent activator by phosphorylation and acetylation. Proc Natl Acad Sci U S A 111:17116-21 |
| Luan, Bing; Goodarzi, Mark O; Phillips, Naomi G et al. (2014) Leptin-mediated increases in catecholamine signaling reduce adipose tissue inflammation via activation of macrophage HDAC4. Cell Metab 19:1058-65 |
| Ravnskjaer, Kim; Hogan, Meghan F; Lackey, Denise et al. (2013) Glucagon regulates gluconeogenesis through KAT2B- and WDR5-mediated epigenetic effects. J Clin Invest 123:4318-28 |
| Tsai, Wen-Wei; Niessen, Sherry; Goebel, Naomi et al. (2013) PRMT5 modulates the metabolic response to fasting signals. Proc Natl Acad Sci U S A 110:8870-5 |
| Luo, Qianyi; Viste, Kristin; Urday-Zaa, Janny Concha et al. (2012) Mechanism of CREB recognition and coactivation by the CREB-regulated transcriptional coactivator CRTC2. Proc Natl Acad Sci U S A 109:20865-70 |
| Wang, Yiguo; Li, Gang; Goode, Jason et al. (2012) Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes. Nature 485:128-32 |
| Wang, Biao; Moya, Noel; Niessen, Sherry et al. (2011) A hormone-dependent module regulating energy balance. Cell 145:596-606 |
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