1,721,099 research outputs found
MicroRNA: Basic mechanisms and transcriptional regulatory networks for cell fate determination
No full textCharacterization of regulatory mechanisms affecting microRNA (miRNA) expression and activity is providing novel clues for the identification of genes and complex regulatory circuits that determine cell and tissue specificity. Here, we review the molecular events leading to miRNA biogenesis and activity, focusing above all on endogenous and epigenetic transcriptional networks involving miRNA in early development, cellular lineage specification/differentiation of nervous, skeletal and cardiac muscle tissues and in haematopoiesis, as the de-regulation of such networks may be relevant to disease pathogenesis
Epigenetic plasticity of chromatin in embryonic and hematopoietic stem/progenitor cells: therapeutic potential of cell reprogramming
No full textDuring embryonic development and adult life, the plasticity and reversibility of modifications that affect the chromatin structure is important in the expression of genes involved in cell fate decisions and the maintenance of cell-differentiated state. Epigenetic changes in DNA and chromatin, which must occur to allow the accessibility of transcriptional factors at specific DNA-binding sites, are regarded as emerging major players for embryonic and hematopoietic stem cell (HSC) development and lineage differentiation. Epigenetic deregulation of gene expression, whether it be in conjunction with chromosomal alterations and gene mutations or not, is a newly recognized mechanism that leads to several diseases, including leukemia. The reversibility of epigenetic modifications makes DNA and chromatin changes attractive targets for therapeutic intervention. Here we review some of the epigenetic mechanisms that regulate gene expression in pluripotent embryonic and multipotent HSCs but may be deregulated in leukemia, and the clinical approaches designed to target the chromatin structure in leukemic cells
Hyperplasia and squamous metaplasia in the tracheobronchial epithelium: alterations in the balance of growth and differentiation factors.
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Oncoproteins, heterochromatin silencing and microRNAs: A new link for leukemogenesis
No full textThe pathogenesis of acute myeloid leukemias involves complex molecular events triggered by diverse alterations of genomic DNA. A limited number of initiating lesions, such as chromosomal translocations generating fusion genes, are constantly identified in specific forms of leukemia and are critical to leukemogenesis. Leukemia fusion proteins derived from chromosomal translocations can mediate epigenetic silencing of gene expression. Epigenetic deregulation of the DNA methylation status and of the chromatin "histone code" at specific gene sites cooperate in the pathogenesis of leukemias. The neutralization of these crucial oncogenic events can revert the leukemia phenotype. Thus, their identification and the study of their molecular and biological consequences is essential for the development of novel and specific therapeutic strategies. In this context, we recently reported a link between the differentiation block of leukemia and the epigenetic silencing of the microRNA-223 gene by the AML1/ETO oncoprotein, the product of the t(8;21) the commonest AML-associated chromosomal translocation. This finding indicates microRNAs as additional epigenetic targets for leukemogenesis and for therapeutic intervention in leukemias. © 2008 Landes Bioscience
Positive and negative regulation of proliferation and differentiation in tracheobronchial epithelial cells.
No full textThe lung (in particular the bronchial epithelium) is a major site for tumor formation in humans. Environmental factors in conjunction with genetic factors are important determinants in this disease. The acquisition of defects in the control of proliferation and differentiation appears to constitute crucial steps in the transition of a normal to a neoplastic cell. Several factors have been identified that control positively or negatively the proliferation and differentiation of tracheobronchial epithelial cells. These factors include EGF/TGF alpha, TGF beta, insulin/IGFI, KGF, certain cytokines, retinoids, and activators of protein kinase C. Studies with neoplastic cells have identified several protooncogenes and tumor suppressor genes whose gene products are involved in the regulation of cell growth of normal tracheobronchial epithelial cells, and when mutated, lost, or activated, bring about a neoplastic phenotype. Future studies on the precise function of these genes will help to elucidate the mechanisms by which proliferation and differentiation in normal tracheobronchial epithelial cells are regulated and help to understand the molecular changes involved in diseases such as cancer
Regulation of type I and type II transglutaminase in normal human bronchial epithelial and lung carcinoma cells.
No full textIn cultured, undifferentiated normal human bronchial epithelial (HBE) cells, transglutaminase activity was localized predominantly in the cytosolic fraction of cell lysates. Upon squamous differentiation, this cytosolic activity declined and was replaced by a 40-fold increase in the activity of particulate (membrane-associated) transglutaminase. Immunoblot analysis demonstrated that the cytosolic transglutaminase was Type II (tissue) transglutaminase and that squamous differentiation shifted gene expression to the Type I (epidermal) transglutaminase. Retinoic acid, an inhibitor of squamous cell differentiation, suppressed the increase in Type I transglutaminase. The decrease in Type II transglutaminase activity was unaffected by retinoic acid. Transforming growth factor-beta 1 (TGF-beta 1) enhanced Type II transglutaminase activity about 10-fold in the undifferentiated cells but did not increase Type I transglutaminase or cholesterol sulfate, two early markers of squamous differentiation. TGF-beta 2 was equivalent to TGF-beta 1 in inducing Type II transglutaminase and in inhibiting the growth of HBE cells. The differentiation-related and TGF-beta-induced changes in transglutaminase activity were reflected in the level of transglutaminase Type I and Type II protein and mRNA. Expression of transglutaminases in lung carcinoma cell lines was variable. No correlation was observed between the expression of Type I transglutaminase and the classification of the cells as squamous cell carcinoma. Several lung carcinoma cell lines exhibited high levels of Type II transglutaminase activity that were increased several-fold by TGF-beta 1 treatment. Retinoic acid was ineffective in altering transglutaminase expression in most cell lines but induced Type II transglutaminase in a time- and dose-dependent manner in NCI-HUT-460 cells
Homeobox 1.3 expression: induction by retinoic acid in human bronchial fibroblasts.
No full textHomeobox (Hox) genes code for transcriptional factors and are expressed during many developmental and differentiative processes. In this study, we describe the induction of Hox 1.3 expression by retinoic acid (RA) in human bronchial fibroblasts (HBF) derived from explants of bronchial tissue. Using Northern blot analysis, we show that RA induces Hox 1.3 mRNA 3- to 10-fold over steady-state levels within 2 h after addition of RA to HBF culture medium. The induction was dose dependent, reaching a half-maximal level at approximately 10(-8) M RA. This induction was not seen in human dermal fibroblasts. Immunofluorescent staining of HBF showed a corresponding increase in Hox 1.3 protein levels in the nuclei. The increase in Hox 1.3 transcript levels in HBF was not abolished by cycloheximide treatment, suggesting that synthesis of a protein intermediate is not required for the induction. RA did not significantly alter the rate of degradation of the Hox 1.3 mRNA as determined by actinomycin D treatment, suggesting that the increase in Hox 1.3 mRNA may be due to an increase in the rate of transcription. This study provides further evidence that bronchial fibroblasts are targets for RA. Although downstream target genes for Hox 1.3 have not yet been identified, it is likely that the induction of Hox 1.3 by RA is an early step in a cascade of RA-induced changes in gene expression in bronchial fibroblasts
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