Abstract
Activating transcription factor 3 (ATF3) is a member of the ATF/cAMP-response element-binding protein family of transcription factors. It is a transcriptional repressor, and the expression of its corresponding gene is induced by stress signals in a variety of tissues, including the liver. In this report, we demonstrate that ATF3 is induced in the pancreas by partial pancreatectomy, streptozotocin treatment, and ischemia coupled with reperfusion. Furthermore, ATF3 is induced in cultured islet cells by oxidative stress. Interestingly, transgenic mice expressing ATF3 in the liver and pancreas under the control of the transthyretin promoter have defects in glucose homeostasis and perinatal lethality. We present evidence that expression of ATF3 in the liver represses the expression of genes encoding gluconeogenic enzymes. Furthermore, expression of ATF3 in the pancreas leads to abnormal endocrine pancreas and reduced numbers of hormone-producing cells. Analyses of embryos indicated that the ATF3 transgene is expressed in the ductal epithelium in the developing pancreas, and the transgenic pancreas has fewer mitotic cells than the non-transgenic counterpart, providing a potential explanation for the reduction of endocrine cells. Because ATF3 is a stress-inducible gene, these mice may represent a model to investigate the molecular mechanisms for some stress-associated diseases.
Highlights
Activating transcription factor 3 (ATF3) is a member of the ATF/cAMP-response element-binding protein family of transcription factors
Overwhelming evidence indicates that ATF3 is induced by a variety of stress signals, such as in the liver by partial hepatectomy, in the brain by seizure, in the heart by ischemia coupled with reperfusion, and in the skin by wounding; in addition, it is induced in cultured cells by UV, ionizing radiation, Fas antibody, lipopolysaccharide, and cytokines
We demonstrate that ATF3 is induced in the pancreas by stress signals and that transgenic mice expressing ATF3 in the liver and pancreas have impaired glucose homeostasis
Summary
Pancreatic Stress Models—For in vivo stress models, male Harlan Sprague-Dawley rats at the age of 7– 8 weeks were used, and the procedures were performed at Zivic Laboratories (Pittsburgh, PA). RNA from cultured islet cells was isolated by TRIzol according to the procedures from the manufacturer, and RT-PCR was carried out as above using the same primers, which work for both rat (RIN-m cell) and mouse (TC6 cells) samples. Sections were blocked with 10% normal goat serum (Vector Laboratories) in a 0.1% Nonidet P-40/ PBS solution for 30 – 60 min and incubated with primary antibody diluted in the blocking solution for overnight at 4 °C in a humidity chamber, unless indicated otherwise (see modifications below). Detection of insulin in E12.5 embryos required the following modifications: sucrose frozen sections (instead of paraffin sections) were used, and the blocking solution was 10% normal goat serum with the addition of 2% (w/v) blocking powder (Roche Molecular Biochemicals); in addition, the primary antibodies were incubated with the sections at room temperature for overnight. For samples with size less than 5 l, analyses were run on a Kodak Ektachem DT60 II analyzer at the Ohio State University Veterinary Histology Laboratory
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