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Activating transcription factor 3 (ATF3) is a stress-inducible gene and encodes a member of the ATF/CREB family of transcription factors. However, the physiological significance of ATF3 induction by stress signals is not clear. In this report, we describe several lines of evidence supporting a role of ATF3 in stress-induced ␤-cell apoptosis. First, ATF3 is induced in ␤ cells by signals relevant to ␤-cell destruction: proinflammatory cytokines, nitric oxide, and high concentrations of glucose and palmitate. Second, induction of ATF3 is mediated in part by the NF-B and Jun N-terminal kinase/stress-activated protein kinase signaling pathways, two stress-induced pathways implicated in both type 1 and type 2 diabetes. Third, transgenic mice expressing ATF3 in ␤ cells develop abnormal islets and defects secondary to ␤-cell deficiency. Fourth, ATF3 knockout islets are partially protected from cytokine-or nitric oxide-induced apoptosis. Fifth, ATF3 is expressed in the islets of patients with type 1 or type 2 diabetes, and in the islets of nonobese diabetic mice that have developed insulitis or diabetes. Taken together, our results suggest ATF3 to be a novel regulator of stress-induced ␤-cell apoptosis.It is widely accepted that autoimmunity is the main cause of type 1 but not type 2 diabetes. Despite this difference, ␤-cell death plays an important role in the pathophysiological progression of both diseases (15,43,45). On one hand, proinflammatory cytokines (interleukin-1␤ , tumor necrosis factor alpha [TNF-␣], and gamma interferon [IFN-␥]) destroy ␤ cells in the islets of Langerhans, leading to the pathogenesis of type 1 diabetes (11,14,15,42); on the other hand, elevated glucose and free fatty acids (FFAs)-common metabolic abnormalities in type 2 diabetes-induce ␤-cell death, contributing to the progression of the disease (13,32,35,53,62). Emerging evidence indicates that activation of the NF-B and Jun N-terminal kinase/stress-activated protein kinase (JNK/ SAPK) signaling pathways is a key event leading to cell death, when ␤ cells are exposed to these signals: proinflammatory cytokines, elevated glucose, and elevated FFAs (12,15,16,43,49). Furthermore, activation of these pathways has been demonstrated to impair insulin signaling (1,17,18,36) and play a role in type 2 diabetes (63,71). Therefore, these stress-activated signaling pathways constitute a common molecular mechanism in the pathophysiological progression of type 1 and type 2 diabetes.Thus far, inducible nitric oxide (NO) synthase (iNOS), whose expression leads to NO production, is one of the best known target genes for these pathways (14-16, 42, 54). Several lines of evidence indicate that iNOS plays an important role in the pathogenesis of diabetes. (i) iNOS is induced in the islets by cytokines (16) and is expressed in the islets of diabetes prone BB rats (33) and nonobese diabetic (NOD) mice (55,58). (ii) Transgenic mice expressing iNOS in ␤ cells develop ␤-cell destruction and diabetes (60). (iii) ␤ cells lacking functional iNOS are partially protected ...

The alphabeta and gammadelta T lineages are thought to arise from a common precursor; however, the regulation of separation and development of these lineages is not fully understood. We report here that development of alphabeta and gammadelta precursors was differentially affected by elimination of ribosomal protein L22 (Rpl22), which is ubiquitously expressed but not essential for translation. Rpl22 deficiency selectively arrested development of alphabeta-lineage T cells at the beta-selection checkpoint by inducing their death. The death was caused by induction of p53 expression, because p53 deficiency blocked death and restored development of Rpl22-deficient thymocytes. Importantly, Rpl22 deficiency led to selective upregulation of p53 in alphabeta-lineage thymocytes, at least in part by increasing p53 synthesis. Taken together, these data indicate that Rpl22 deficiency activated a p53-dependent checkpoint that produced a remarkably selective block in alphabeta T cell development but spared gammadelta-lineage cells, suggesting that some ribosomal proteins may perform cell-type-specific or stage-specific functions.

In many tissues, the presence of stem cells is inferred by the capacity of the tissue to maintain homeostasis and undergo repair after injury. Isolation of self-renewing cells with the ability to generate the full array of cells within a given tissue strongly supports this idea, but the identification and genetic manipulation of individual stem cells within their niche remain a challenge. Here we present novel methods for marking and genetically altering epithelial follicle stem cells (FSCs) within the Drosophila ovary. Using these new tools, we define a sequential multistep process that comprises transitioning of FSCs from quiescence to proliferation. We further demonstrate that integrins are cell-autonomously required within FSCs to provide directional signals that are necessary at each step of this process. These methods may be used to define precise roles for specific genes in the sequential events that occur during FSC division after a period of quiescence.

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...