Stomach regional specification requiresHoxa5-driven mesenchymal-epithelial signaling

Development ◽  
2002 ◽  
Vol 129 (17) ◽  
pp. 4075-4087 ◽  
Author(s):  
Josée Aubin ◽  
Ugo Déry ◽  
Margot Lemieux ◽  
Pierre Chailler ◽  
Lucie Jeannotte
Keyword(s):  
Growth Factor ◽  
Hox Genes ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Signaling Molecules ◽  
Loss Of Function ◽  
Expression Of Genes ◽  
Molecular Events ◽  
Genes Encoding ◽  
Fibroblast Growth Factor 10

The genetic control of gut regionalization relies on a hierarchy of molecular events in which the Hox gene family of transcription factors is suspected to be key participant. We have examined the role of Hox genes in gut patterning using the Hoxa5–/– mice as a model. Hoxa5 is expressed in a dynamic fashion in the mesenchymal component of the developing gut. Its loss of function results in gastric enzymatic anomalies in Hoxa5–/– surviving mutants that are due to perturbed cell specification during stomach development. Histological, biochemical and molecular characterization of the mutant stomach phenotype may be compatible with a homeotic transformation of the gastric mucosa. As the loss of mesenchymal Hoxa5 function leads to gastric epithelial defects, Hoxa5 should exert its action by controlling molecules involved in mesenchymal-epithelial signaling. Indeed, in the absence of Hoxa5 function, the expression of genes encoding for signaling molecules such as sonic hedgehog, Indian hedgehog, transforming growth factor β family members and fibroblast growth factor 10, is altered. These findings provide insight into the molecular controls of patterning events of the stomach, supporting the notion that Hoxa5 acts in regionalization and specification of the stomach by setting up the proper domains of expression of signaling molecules.

scholarly journals The noncoding MIR100HG RNA enhances the autocrine function of transforming growth factor β signaling

Oncogene ◽  
2021 ◽  
Author(s):  
Panagiotis Papoutsoglou ◽  
Dorival Mendes Rodrigues-Junior ◽  
Anita Morén ◽  
Andrew Bergman ◽  
Fredrik Pontén ◽  
...  
Keyword(s):  
Growth Factor ◽  
Target Genes ◽  
Rna Binding ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tgfβ Signaling ◽  
Ribonucleoprotein Complexes ◽  
Expression Of Genes ◽  
Downstream Effectors ◽  
Human Carcinomas

AbstractActivation of the transforming growth factor β (TGFβ) pathway modulates the expression of genes involved in cell growth arrest, motility, and embryogenesis. An expression screen for long noncoding RNAs indicated that TGFβ induced mir-100-let-7a-2-mir-125b-1 cluster host gene (MIR100HG) expression in diverse cancer types, thus confirming an earlier demonstration of TGFβ-mediated transcriptional induction of MIR100HG in pancreatic adenocarcinoma. MIR100HG depletion attenuated TGFβ signaling, expression of TGFβ-target genes, and TGFβ-mediated cell cycle arrest. Moreover, MIR100HG silencing inhibited both normal and cancer cell motility and enhanced the cytotoxicity of cytostatic drugs. MIR100HG overexpression had an inverse impact on TGFβ signaling responses. Screening for downstream effectors of MIR100HG identified the ligand TGFβ1. MIR100HG and TGFB1 mRNA formed ribonucleoprotein complexes with the RNA-binding protein HuR, promoting TGFβ1 cytokine secretion. In addition, TGFβ regulated let-7a-2–3p, miR-125b-5p, and miR-125b-1–3p expression, all encoded by MIR100HG intron-3. Certain intron-3 miRNAs may be involved in TGFβ/SMAD-mediated responses (let-7a-2–3p) and others (miR-100, miR-125b) in resistance to cytotoxic drugs mediated by MIR100HG. In support of a model whereby TGFβ induces MIR100HG, which then enhances TGFβ1 secretion, analysis of human carcinomas showed that MIR100HG expression correlated with expression of TGFB1 and its downstream extracellular target TGFBI. Thus, MIR100HG controls the magnitude of TGFβ signaling via TGFβ1 autoinduction and secretion in carcinomas.

Profibrogenic phenotype in caveolin-1 deficiency via differential regulation of STAT-1/3 proteins

2014 ◽  
Vol 92 (5) ◽  
pp. 370-378 ◽  
Author(s):  
Stefan W. Ryter ◽  
Augustine M.K. Choi ◽  
Hong Pyo Kim
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Tyrosine Phosphatase ◽  
Transforming Growth Factor Β ◽  
Lung Fibroblasts ◽  
Caveolin 1 ◽  
Expression Of Genes ◽  
Liver And Kidney

Fibrosis underlies the pathogenesis of several human diseases, which can lead to severe injury of vital organs. We previously demonstrated that caveolin-1 expression is reduced in experimental fibrosis and that caveolin-1 exerts antiproliferative and antifibrotic effects in lung fibrosis models. The signal transducers and activators of transcription (STAT) proteins, STAT1 and STAT3, can be activated simultaneously. STAT1 can inhibit cell growth and promote apoptosis while STAT3 inhibits apoptosis. Here, we show that caveolin-1-deficient (cav-1−/−) lung fibroblasts display dramatically upregulated STAT3 activation in response to platelet-derived growth factor-BB and transforming growth factor-β stimuli, whereas STAT1 activation is undetectable. Downregulation of protein tyrosine phosphatase-1B played a role in the preferential activation of STAT3 in cav-1−/− fibroblasts. Genetic deletion of STAT3 by siRNA modulated the expression of genes involved in cell proliferation and fibrogenesis. Basal expression of α-smooth muscle actin was prominent in cav-1−/− liver and kidney, consistent with deposition of collagen in these organs. Collectively, we demonstrate that the antiproliferative and antifibrogenic properties of caveolin-1 in vitro are mediated by the balance between STAT1 and STAT3 activation. Deregulated STAT signaling associated with caveolin-1 deficiency may be relevant to proliferative disorders such as tissue fibrosis.

Transforming growth factor-β-regulated expression of genes in macrophages implicated in the control of cholesterol homoeostasis

2006 ◽  
Vol 34 (6) ◽  
pp. 1141-1144 ◽  
Author(s):  
D.P. Ramji ◽  
N.N. Singh ◽  
P. Foka ◽  
S.A. Irvine ◽  
K. Arnaoutakis
Keyword(s):  
Growth Factor ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Crucial Importance ◽  
Expression Of Genes ◽  
Regulated Expression ◽  
Key Genes

The regulation of macrophage cholesterol homoeostasis is of crucial importance in the pathogenesis of atherosclerosis, an underlying cause of heart attack and stroke. Several recent studies have revealed a critical role for the cytokine TGF-β (transforming growth factor-β), a key regulator of the immune and inflammatory responses, in atherogenesis. We discuss here the TGF-β signalling pathway and its role in this disease along with the outcome of our recent studies on the action of the cytokine on the expression of key genes implicated in the uptake or efflux of cholesterol by macrophages and the molecular mechanisms underlying such regulation.

scholarly journals Secretoglobin 3A2 Suppresses Bleomycin-induced Pulmonary Fibrosis by Transforming Growth Factor β Signaling Down-regulation

2011 ◽  
Vol 286 (22) ◽  
pp. 19682-19692 ◽  
Author(s):  
Reiko Kurotani ◽  
Satoshi Okumura ◽  
Tsutomu Matsubara ◽  
Utako Yokoyama ◽  
John R. Buckley ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Tgfβ Signaling ◽  
Adult Mice ◽  
Cell Counts ◽  
Expression Of Genes ◽  
Pulmonary Airways

With increasing worldwide rates of morbidity and mortality of pulmonary fibrosis, the development of effective therapeutics for this disease is of great interest. Secretoglobin (SCGB) 3A2, a novel cytokine-like molecule predominantly expressed in pulmonary airways epithelium, exhibits anti-inflammatory and growth factor activities. In the current study SCGB3A2 was found to inhibit TGFβ-induced differentiation of fibroblasts to myofibroblasts, a hallmark of the fibrogenic process, using pulmonary fibroblasts isolated from adult mice. This induction was through increased phosphorylation of STAT1 and expression of SMAD7 and decreased phosphorylation of SMAD2 and SMAD3. To demonstrate the effect of SCGB3A2 on the TGFβ signaling in vivo, a bleomycin-induced pulmonary fibrosis mouse model was used. Mice were administered bleomycin intratracheally followed by intravenous injection of recombinant SCGB3A2. Histological examination in conjunction with inflammatory cell counts in bronchoalveolar lavage fluids demonstrated that SCGB3A2 suppressed bleomycin-induced pulmonary fibrosis. Microarray analysis was carried out using RNAs from lungs of bleomycin-treated mice with or without SCGB3A2 and normal mice treated with SCGB3A2. The results demonstrated that SCGB3A2 affects TGFβ signaling and reduces the expression of genes involved in fibrosis. This study suggests the potential utility of SCGB3A2 for targeting TGFβ signaling in the treatment of pulmonary fibrosis.

scholarly journals The Forkhead Box M1 Transcription Factor Is Essential for Embryonic Development of Pulmonary Vasculature

2005 ◽  
Vol 280 (23) ◽  
pp. 22278-22286 ◽  
Author(s):  
Il-Man Kim ◽  
Sneha Ramakrishna ◽  
Galina A. Gusarova ◽  
Helena M. Yoder ◽  
Robert H. Costa ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Pulmonary Vasculature ◽  
Matrix Remodeling ◽  
Knock Out ◽  
Forkhead Box ◽  
Forkhead Box M1 ◽  
Expression Of Genes

Transgenic and gene knock-out studies demonstrated that the mouse Forkhead Box m1 (Foxm1 or Foxm1b) transcription factor (previously called HFH-11B, Trident, Win, or MPP2) is essential for hepatocyte entry into mitosis during liver development, regeneration, and liver cancer. Targeted deletion of Foxm1 gene in mice produces an embryonic lethal phenotype due to severe abnormalities in the development of liver and heart. In this study, we show for the first time that Foxm1–/– lungs exhibit severe hypertrophy of arteriolar smooth muscle cells and defects in the formation of peripheral pulmonary capillaries as evidenced by significant reduction in platelet endothelial cell adhesion molecule 1 staining of the distal lung. Consistent with these findings, significant reduction in proliferation of the embryonic Foxm1–/– lung mesenchyme was found, yet proliferation levels were normal in the Foxm1-deficient epithelial cells. Severe abnormalities of the lung vasculature in Foxm1–/– embryos were associated with diminished expression of the transforming growth factor β receptor II, a disintegrin and metalloprotease domain 17 (ADAM-17), vascular endothelial growth factor receptors, Polo-like kinase 1, Aurora B kinase, laminin α4 (Lama4), and the Forkhead Box f1 transcription factor. Cotransfection studies demonstrated that Foxm1 stimulates transcription of the Lama4 promoter, and this stimulation requires the Foxm1 binding sites located between –1174 and –1145 bp of the mouse Lama4 promoter. In summary, development of mouse lungs depends on the Foxm1 transcription factor, which regulates expression of genes essential for mesenchyme proliferation, extracellular matrix remodeling, and vasculogenesis.

Molecular embryology of the lung: then, now, and in the future

1999 ◽  
Vol 276 (5) ◽  
pp. L697-L704 ◽  
Author(s):  
David Warburton ◽  
Jingsong Zhao ◽  
Mary Anne Berberich ◽  
Merton Bernfield
Keyword(s):  
Growth Factor ◽  
Transcriptional Activation ◽  
Transforming Growth Factor ◽  
Gene Families ◽  
Transforming Growth Factor Β ◽  
Branching Morphogenesis ◽  
Limb Bud ◽  
Loss Of Function ◽  
New Therapeutic Approaches ◽  
Extracellular Matrix Components

Complementary molecular and genetic approaches are yielding information about gain- versus loss-of-function phenotypes of specific genes and gene families in the embryonic, fetal, neonatal, and adult lungs. New insights are being derived from the conservation of function between genes regulating branching morphogenesis of the respiratory organs in Drosophila and in the mammalian lung. The function of specific morphogenetic genes in the lung are now placed in context with pattern-forming functions in other, better understood morphogenetic fields such as the limb bud. Initiation of lung morphogenesis from the floor of the primitive foregut requires coordinated transcriptional activation and repression involving hepatocyte nuclear factor-3β, Sonic hedgehog, patched, Gli2, and Gli3 as well as Nkx2.1. Subsequent inductive events require epithelial-mesenchymal interaction mediated by specific fibroblast growth factor ligand-receptor signaling as well as modulation by other peptide growth factors including epidermal growth factor, platelet-derived growth factor-A and transforming growth factor-β and by extracellular matrix components. A scientific rationale for developing new therapeutic approaches to urgent questions of human pulmonary health such as bronchopulmonary dysplasia is beginning to emerge from work in this field.

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