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.Stress signals elicit a variety of cellular responses. Some responses such as that of heat shock have been demonstrated to be protective (1), whereas others such as inflammatory responses have been demonstrated to be detrimental (2-4). The balance between the protective and detrimental events determines the net outcome. We have been investigating a stressinducible gene, Activating transcription factor 3 (ATF3).1 ATF3 is a member of the ATF/cAMP-responsive element binding protein family of basic region-leucine zipper (bZip) transcription factors (reviewed in Refs. 5-10). Although ATF3 was isolated from a human library (11), homologous genes from rats and mice with about 95% identity to ATF3 at the amino acid level have been identified: LRF-1 in the rat (12) and LRG-21 (13), CRG-5 (14), or TI-241 (15) in the mouse. For the convenience of discussion, we will use the ATF3 nomenclature in the rest of this report. 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 (ischemia-reperfusion), and in the skin by wounding; in addition, it is induced in cultured cells by UV, ionizing radiation, Fas antibody, lipopolysaccharide, and cytokines (reviewed in Refs. 5, 6). Therefore, ATF3 is induced in many tissues by a variety of stress signals, suggesting that it is a key regulator in cellular stress responses.Despite overwhelming evidence indicating that ATF3 is a stress-inducible gene, the physiological consequence of expressing ATF3 is not clear. In this report, we demonstrate that ATF3 is induced in the pancr...

Activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element-binding protein family of transcription factors, is a transcriptional repressor, and the expression of its corresponding gene, ATF3, is induced by many stress signals. In this report, we demonstrate that transgenic mice expressing ATF3 in the liver had symptoms of liver dysfunction such as high levels of serum bilirubin, alkaline phosphatase, alanine transaminase, aspartate transaminase, and bile acids. In addition, these mice had physiological responses consistent with hypoglycemia including a low insulin:glucagon ratio in the serum and reduced adipose tissue mass. Electrophoretic mobility shift assays indicated that ATF3 bound to the ATF/cAMP-responsvie element site derived from the promoter of the gene encoding the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK). Furthermore, transient transfection assays indicated that ATF3 repressed the activity of the PEPCK promoter. Taken together, our results are consistent with the model that the expression of ATF3 in the liver results in defects in glucose homeostasis by repressing gluconeogenesis. Because ATF3 is a stressinducible gene, these mice may provide a model to investigate the molecular mechanisms of some stressassociated liver diseases.