The endocrine cells of the rat pancreatic islets of Langerhans, including insulin-producing -cells, turn over every 40 -50 days by processes of apoptosis and the proliferation and differentiation of new islet cells (neogenesis) from progenitor epithelial cells located in the pancreatic ducts. However, the administration to rats of islet trophic factors such as glucose or glucagon-like peptide 1 for 48 h results in a doubling of islet cell mass, suggesting that islet progenitor cells may reside within the islets themselves. Here we show that rat and human pancreatic islets contain a heretofore unrecognized distinct population of cells that express the neural stem cell-specific marker nestin. Nestin-positive cells within pancreatic islets express neither the hormones insulin, glucagon, somatostatin, or pancreatic polypeptide nor the markers of vascular endothelium or neurons, such as collagen IV and galanin. Focal regions of nestinpositive cells are also identified in large, small, and centrolobular ducts of the rat pancreas. Nestin-positive cells in the islets and in pancreatic ducts are distinct from ductal epithelium because they do not express the ductal marker cytokeratin 19 (CK19). After their isolation, these nestin-positive cells have an unusually extended proliferative capacity when cultured in vitro (ϳ8 months), can be cloned repeatedly, and appear to be multipotential. Upon confluence, they are able to differentiate into cells that express liver and exocrine pancreas markers, such as ␣-fetoprotein and pancreatic amylase, and display a ductal/endocrine phenotype with expression of CK19, neural-specific cell adhesion molecule, insulin, glucagon, and the pancreas/duodenum specific homeodomain transcription factor, IDX-1. We propose that these nestin-positive islet-derived progenitor ( T he mammalian pancreas consists of three distinct tissue types: the ductal tree, the exocrine acini that produce digestive enzymes, and the endocrine islets of Langerhans. Embedded in the exocrine tissue are the islets (which contain ␣-, -, ␦-, and PP-cells that produce the hormones glucagon, insulin, somatostatin, and pancreatic polypeptide, respectively) involved in the regulation of physiological nutrient homeostasis (1). Ductal cells of the adult pancreas include latent progenitor cells of the islet endocrine cells that can be induced to differentiate into islet endocrine cells given the appropriate morphogen stimuli-a process referred to as neogenesis (2-6). The differentiation of duct cells of the pancreas into endocrine hormone-producing cells is believed to recapitulate the embryonic development (ontogeny) of the pancreas, whereby the exocrine and endocrine pancreases arise from the differentiation and proliferation of patterned endodermal cells in the early embryonic foregut that first form a ductal tree by branching morphogenesis (1). During early embryonic development, neural and islet cells share many phenotypic properties. Developing islet cells express several neuronal-specific markers such as synaptophysins,...
Repeated exposure to psychomotor stimulants produce long-term changes in behavior ranging from addiction to behavioral sensitization. Many of these behaviors depend on the nigrostriatal system of the basal ganglia. We show here that chronic cocaine exposure not only leads to time-varying alterations in the inducibility of bZIP transcription factors in individual striatal neurons, but also to long-lasting network changes in which ensembles of striatal neurons express these proteins. These network-level adaptations suggest that the behavioral sensitization induced by repeated psychomotor stimulant exposure may reflect an enduring functional reorganization of basal ganglia circuits.
Members of the C/EBP family of basicleucine zipper (bZip) transcription factors form heterodimers and bind to the CAAT box and other sequence-related enhancer motifs. Using a 32P-labeled protein probe consisting of the bZip domain of C/EBPI3, we isolated a clone encoding C/EBP-related ATF (C/ATF), a bZip protein that heterodimerizes with C/EBP-like proteins but belongs to the CREB/ATF family. C/ATF homodimers do not bind to typical C/EBP DNA sites. Instead they bind to palindromic cAMP response elements such as that of the somatostatin gene.In addition, C/ATF-C/EBPP heterodimers bind to a subclass of asymmetric cAMP response elements exemplified by those in the phosphoenolpyruvate carboxykinase and proenkephalin genes. Transient transfection studies indicate that interactions between C/ATF and C/EBP,B are the basis for a functional cross talk between these two families of transcription factors that may be important for the integration of hormonal and developmental stimuli that determine the expression of subsets of genes in specific cellular phenotypes.A predominant mechanism of control of gene expression in response to extracellular or intracellular cues occurs at the transcriptional level by the binding of cell-specific and ubiquitous transactivating nuclear proteins to their cognate DNA regulatory elements. Transcription factors that are widely distributed amongst cells of different phenotypes utilize a combinatorial mechanism that ultimately determines the transcriptional activities of specific genes.Distinct classes of transcription factors have been defined based on their structural relatedness. One of these classes is characterized by conserved basic-leucine zipper (bZip) domains required for DNA recognition and binding and for protein dimerization (1). The bZip transcription factors can be grouped into three major families based on the similarities of their structures, their capability to associate as homodimers or as heterodimers with other members ofthe same family, and their DNA-binding specificities. One of these families is composed of CREB/activating transcription factor (ATF) proteins, which bind to cAMP response element (CRE) sequences and are involved in the modulation of the transcriptional responses induced by cAMP or by certain viral proteins (2, 3). Another family is that of Fos-and Jun-related oncoproteins (4). The third family is composed of CAAT box/enhancer-binding proteins (C/EBPs) (5, 6), which bind to CAAT-box and related enhancer motifs and regulate the expression of genes during cellular differentiation or in response to inflammatory cytokines. Interactions of bZip proteins within each subfamily are restricted and dictated by a specific and complex dimerization code.Here we report the identification of C/EBP-related ATF
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