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Transcriptional Program (transcriptional + program)
Selected AbstractsThe regulation of the endosomal compartment by p53 the tumor suppressor geneFEBS JOURNAL, Issue 8 2009Xin Yu The endosomal compartment of the cell is involved in a number of functions including: (a) internalizing membrane proteins to multivesicular bodies and lysosomes; (b) producing vesicles that are secreted from the cell (exosomes); and (c) generating autophagic vesicles that, especially in times of nutrient deprivation, supply cytoplasmic components to the lysosome for degradation and recycling of nutrients. The p53 protein responds to various stress signals by initiating a transcriptional program that restores cellular homeostasis and prevents the accumulation of errors in a cell. As part of this process, p53 regulates the transcription of a set of genes encoding proteins that populate the endosomal compartment and impact upon each of these endosomal functions. Here, we demonstrate that p53 regulates transcription of the genes TSAP6 and CHMP4C, which enhance exosome production, and CAV1 and CHMP4C, which produce a more rapid endosomal clearance of the epidermal growth factor receptor from the plasma membrane. Each of these p53-regulated endosomal functions results in the slowing of cell growth and division, the utilization of catabolic resources and cell-to-cell communication by exosomes after a stress signal is detected by the p53 protein. These processes avoid errors during stress and restore homeostasis once the stress is resolved. [source] Adipogenic Phenotype of Hepatic Stellate CellsALCOHOLISM, Issue 2005Hide Tsukamoto Abstract: Transdifferentiation of hepatic stellate cells (HSC) constitutes a major cellular event in the genesis of alcoholic liver fibrosis and cirrhosis and molecular mechanisms underlying this process is incompletely understood. Our laboratory proposed several years ago that HSC quiescence requires the transcriptional program known to be integral to preadipocyte to adipocyte differentiation. In support of the hypothesis, our research demonstrates the expression of adipogenic transcription factors (C/EBPs, PPAR,, SREBP-1c, LXR,) and adipocyte-specific genes (adipsin, resistin) are high in quiescent HSC and depleted in activated HSC. Three gain-of-function approaches have been taken to test this notion: the treatment of activated HSC with the adipocyte differentiation cocktail; ectopic expression of PPAR, or SREBP-1c. All three treatments coordinately upregulate a panel of putative adipogenic transcrition factors and cause morphologic and biochemical reversal of activated HSC to quiescent cells. These findings establish a new conceptual framework for the treatment of liver fibrosis and propose an intriguing notion concerning the plasticity of HSC. [source] Modulation of gene expression by extracellular pH variations in human fibroblasts: A transcriptomic and proteomic studyPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 5 2003Maja A. Bumke Abstract Homeostasis of the intracellular ionic concentration, in particular that of hydrogen ions, is pivotal to the maintenance of cell function and viability. Nonetheless, pH fluctuations in both the intracellular and the extracellular compartments can occurr during development, in physiological processes and in disease. The influence of pH variations on gene expression has been studied in different model systems, but only for a limited number of genes. We have performed a broad range analysis of the patterns of gene expression in normal human dermal fibroblasts at two different pH values (in the presence and in the absence of serum), with the aim of getting a deeper insight into the regulation of the transcriptional program as a response to a pH change. Using the Affymetrix gene chip system, we found that the expression of 2068 genes (out of 12,565) was modulated by more than two-fold at 24, 48 or 72 h after the shift of the culture medium pH to a more acidic value, stanniocalcin 1 being a remarkable example of a strongly up-regulated gene. Genes displaying a modulated pattern of expression included, among others, cell cycle regulators (consistent with the observation that acidic pH abolishes the growth of fibroblasts in culture) and relevant extracellular matrix (ECM) components. Extracellular matrix protein 2, a protein with a restricted pattern of expression in adult human tissues, was found to be remarkably overexpressed as a consequence of serum starvation. Since ECM components, whose expression is controlled by pH, have been used as targets for biomolecular intervention, we have complemented the Affymetrix analysis with a two-dimensional polyacrylamide gel electrophoresis analysis of proteins which are differentially secreted by fibroblasts at acidic or basic pH. Mass spectrometric analysis of more than 650 protein spots allowed the identification of 170 protein isoforms or fragments, belonging to 40 different proteins. Some proteins were only expressed at basic pH (including, for instance, tetranectin), while others (e.g., agrin) were only detectable at acidic pH. Some of the identified proteins may represent promising candidate targets for biomedical applications, e.g., for antibody-mediated vascular targeting strategies. [source] Identification of the Tctex-1 regulatory element that directs expression to neural stem/progenitor cells in developing and adult brainTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 16 2010Yun-Yu Tseng Abstract Previous studies showed that Tctex-1 immunoreactivity is selectively enriched in the germinal zones of adult brain. In this report we identify a regulatory region of the Tctex-1 gene that is capable of directing transgenic expression of green fluorescent protein (GFP) reporter that recapitulates the spatial and temporal expression pattern of endogenous Tctex-1. This construct specifically targeted expression to the nestin+/Pax6+/GLAST+ radial glial cells and Tbr2+ intermediate progenitors when the reporter construct was delivered to developing mouse neocortex via in utero electroporation. Characterization of mice transgenically expressing GFP under the same regulatory element showed that the GFP expression is faithful to endogenous Tctex-1 at the subgranular zone (SGZ) of dentate gyrus, ventricular/subventricular zone of lateral ventricles, and ependymal layer of 3rd ventricle of adult brains. Immunolocalization and bromodeoxyuridine incorporation studies of adult SGZ in four independent mouse lines showed that Tctex-1:GFP reporter selectively marks nestin+/GFAP+/Sox2+ neural stem-like cells in two mouse lines (4 and 13). In two other mouse lines (17 and 18), Tctex-1:GFP is selectively expressed in Type-2 and Type-3 transient amplifying progenitors and a small subset of young neuronal progeny. The P/E-Tctex-1 reporter mouse studies independently confirmed the specific enrichment of Tctex-1 at adult SGZ stem/progenitor cells. Furthermore, these studies supported the notion that an analogous transcriptional program may be used to regulate neurogenesis in embryonic cerebral cortex and adult hippocampus. Finally, the genomic sequences and the reporter mouse lines described here provide useful experimental tools to advance adult neural stem cell research. J. Comp. Neurol. 518:3327,3342, 2010. © 2010 Wiley-Liss, Inc. [source] Transcriptional profiling of brain-derived-neurotrophic factor-induced neuronal plasticity: A novel role for nociceptin in hippocampal neurite outgrowthDEVELOPMENTAL NEUROBIOLOGY, Issue 4 2006Robert H. Ring Abstract Brain derived neurotrophic factor (BDNF) exhibits a sequence of actions on neurons ranging from acute enhancement of transmission to long-term promotion of neurite outgrowth and synaptogenesis associated with learning and memory. The manifold effects of BDNF on neuronal modifications may be mediated by genomic alterations. We previously found that BDNF treatment acutely increases transcription of the synaptic vesicle protein Rab3A, required for trophin-induced synaptic plasticity, as well as the peptide VGF, which increases during learning. To elucidate comprehensive transcriptional programs associated with short- and long-term BDNF exposure, we now examine mRNA abundance and complexity using Affymetrix GeneChips in cultured hippocampal neurons. Consistent with the modulation of synaptic plasticity, BDNF treatment (3,6 h) induced mRNAs encoding the synapse-associated proteins synaptojanin 2, neuronal pentraxin 1, septin 9, and ryanodine receptor 2. BDNF also induced expression of mRNAs encoding neuropeptides (6,12 h), including prepronociceptin, neuropeptide Y, and secretogranin. To determine whether these neuropeptides induced by BDNF mediate neuronal development, we examined their effects on hippocampal neurons. The four mature peptides derived from post-translational processing of the ppNociceptin propeptide induced the expression of several immediate early genes in hippocampal cultures, indicating neuronal activation. To examine the significance of activation, the effects of nociceptin (orphanin FQ) and nocistatin on neurite outgrowth were examined. Quantitative morphometric analysis revealed that nociceptin significantly increased both average neurite length and average number of neurites per neuron, while nocistatin had no effect on these parameters. These results reveal a novel role for nociceptin and suggest that these neuropeptide systems may contribute to the regulation of neuronal function by BDNF. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006 [source] On the diabetic menu: Zebrafish as a model for pancreas development and functionBIOESSAYS, Issue 2 2009Mary D. Kinkel Abstract Development of the vertebrate pancreas is a complex stepwise process comprising regionalization, cell differentiation, and morphogenesis. Studies in zebrafish are contributing to an emerging picture of pancreas development in which extrinsic signaling molecules influence intrinsic transcriptional programs to allow ultimate differentiation of specific pancreatic cell types. Zebrafish experiments have revealed roles for several signaling molecules in aspects of this process; for example our own work has shown that retinoic acid signals specify the pre-pancreatic endoderm. Time-lapse imaging of live zebrafish embryos has started to provide detailed information about early pancreas morphogenesis. In addition to modeling embryonic development, the zebrafish has recently been used as a model for pancreas regeneration studies. Here, we review the significant progress in these areas and consider the future potential of zebrafish as a diabetes research model. 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