Linked Life Data

21749980

Source:http://linkedlifedata.com/resource/pubmed/id/21749980

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2011-7-13
pubmed:abstractText
Notch is an ancient cell-signaling system that regulates the specification of cell fate. This study examined the role of Notch in the epithelial-mesenchymal transition (EMT) and myofibroblast differentiation of cultured RLE-6TN cells (i.e., rat alveolar epithelial cells). The activation of Notch, either by ectopic expression of the Notch intracellular domain or by the co-culture of RLE-6TN cells with L-Jagged1 cells, induces the expression of smooth muscle ?-actin (SMA) and other mesenchymal marker genes (collagen I and vimentin), and reduces the expression of epithelial marker genes (E-cadherin, occludin, and zonula occludens-1). The pharmacologic inhibition of the endogenous Notch signal significantly inhibited the transforming growth factor-? (TGF-?)-induced expression of SMA. Cell migratory capacity was increased by Notch. Luciferase assays revealed that the CC(A/T)(6)GG (CArG) box and the TGF-? control element (TCE) are required for Notch-induced SMA gene transcription. DNA microarray analysis revealed that members of the TGF-? family as well as Jagged1 were induced in RLE-6TN cells by Notch. Western blot analysis showed that Notch induced the phosphorylation of Smad3, and the TGF-? receptor type I/activin receptor-like kinase 5 (ALK5) kinase inhibitor SB431542 markedly reduced the Notch-induced expression of SMA. Enzyme-linked immunosorbent assays confirmed the production of TGF-?1 from RLE-6TN cells by Notch. Immunohistochemistry of a bleomycin-induced model of pulmonary fibrosis and lung specimens from patients with idiopathic interstitial pneumonias showed that Notch was strongly expressed in myofibroblasts, identified as SMA-positive cells. These data indicate that Notch induces myofibroblast differentiation through a TGF-?-Smad3 pathway that activates SMA gene transcription in a CArG-dependent and TCE-dependent manner in alveolar epithelial cells. Our data also imply that Notch induces the EMT phenotype, with increased migratory behavior in pulmonary fibrosis.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
1535-4989
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
45
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
136-44
pubmed:meshHeading
pubmed-meshheading:21749980-Animals, pubmed-meshheading:21749980-Antigens, Differentiation, pubmed-meshheading:21749980-Cell Line, pubmed-meshheading:21749980-Cell Movement, pubmed-meshheading:21749980-Coculture Techniques, pubmed-meshheading:21749980-Epithelial-Mesenchymal Transition, pubmed-meshheading:21749980-Fibroblasts, pubmed-meshheading:21749980-Gene Expression Regulation, pubmed-meshheading:21749980-Male, pubmed-meshheading:21749980-Myoblasts, pubmed-meshheading:21749980-Phosphorylation, pubmed-meshheading:21749980-Pulmonary Alveoli, pubmed-meshheading:21749980-Pulmonary Fibrosis, pubmed-meshheading:21749980-Rats, pubmed-meshheading:21749980-Rats, Wistar, pubmed-meshheading:21749980-Receptors, Notch, pubmed-meshheading:21749980-Response Elements, pubmed-meshheading:21749980-Signal Transduction, pubmed-meshheading:21749980-Smad3 Protein, pubmed-meshheading:21749980-Transforming Growth Factor beta1
pubmed:year
2011
pubmed:articleTitle
Notch induces myofibroblast differentiation of alveolar epithelial cells via transforming growth factor-{beta}-Smad3 pathway.
pubmed:affiliation
Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8511, Japan.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't