| Mechanisms of TGFbeta inhibition of LUNG endodermal morphogenesis: the role of TbetaRII, Smads, Nkx2.1 and Pten. | |
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MedLine Citation:
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PMID: 18602626 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Transforming growth factor-beta is a multifunctional growth factor with roles in normal development and disease pathogenesis. One such role is in inhibition of lung branching morphogenesis, although the precise mechanism remains unknown. In an explant model, all three TGFbeta isoforms inhibited FGF10-induced morphogenesis of mesenchyme-free embryonic lung endoderm. Inhibition of budding by TGFbeta was partially abrogated in endodermal explants from Smad3(-/-) or conditional endodermal-specific Smad4(Delta/Delta) embryonic lungs. Endodermal explants from conditional TGFbeta receptor II knockout lungs were entirely refractive to TGFbeta-induced inhibition. Inhibition of morphogenesis was associated with dedifferentiation of endodermal cells as documented by a decrease in key transcriptional factor, NKX2.1 protein, and its downstream target, surfactant protein C (SpC). TGFbeta reduced the proliferation of wild-type endodermal cells within the explants as assessed by BrdU labeling. Gene expression analysis showed increased levels of mRNA for Pten, a key regulator of cell proliferation. Conditional, endodermal-specific deletion of Pten overcame TGFbeta's inhibitory effect on cell proliferation, but did not restore morphogenesis. Thus, the mechanisms by which TGFbeta inhibits FGF10-induced lung endodermal morphogenesis may entail both inhibition of cell proliferation, through increased Pten, as well as inhibition or interference with morphogenetic mediators such as Nkx2.1. Both of the latter are dependent on signaling through TbetaRII. |
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Authors:
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Yiming Xing; Changgong Li; Lingyan Hu; Caterina Tiozzo; Min Li; Yang Chai; Saverio Bellusci; Stewart Anderson; Parviz Minoo |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2008-05-13 |
Journal Detail:
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Title: Developmental biology Volume: 320 ISSN: 1095-564X ISO Abbreviation: Dev. Biol. Publication Date: 2008 Aug |
Date Detail:
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Created Date: 2008-08-04 Completed Date: 2008-09-09 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 0372762 Medline TA: Dev Biol Country: United States |
Other Details:
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Languages: eng Pagination: 340-50 Citation Subset: IM |
Affiliation:
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Department of Pediatrics, Division of Neonatology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Endoderm / embryology* Humans Lung / embryology* Mice Mice, Mutant Strains Morphogenesis* Nuclear Proteins / physiology* PTEN Phosphohydrolase / physiology* Protein-Serine-Threonine Kinases / physiology* Receptors, Transforming Growth Factor beta / physiology* Smad Proteins, Receptor-Regulated / physiology Smad3 Protein Smad4 Protein Transcription Factors / physiology* Transforming Growth Factor beta1 / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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R01 HL056590-12/HL/NHLBI NIH HHS; R01 HL073471-01A1/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Nuclear Proteins; 0/Receptors, Transforming Growth Factor beta; 0/Smad Proteins, Receptor-Regulated; 0/Smad3 Protein; 0/Smad4 Protein; 0/TGFB1 protein, human; 0/Transcription Factors; 0/Transforming Growth Factor beta1; 0/thyroid nuclear factor 1; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.30/transforming growth factor-beta type II receptor; EC 3.1.3.48/Pten protein, mouse; EC 3.1.3.67/PTEN Phosphohydrolase |
| Comments/Corrections | |
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