title: Signaling pathway by which TGF-beta1 increases expression of latent TGF-beta binding protein-2 at the transcriptional level.
abstract: The cytokine transforming growth factor-beta has multiple effects on a wide variety of cell types. These effects include modulation of growth and regulation of gene transcription. In the present work, we demonstrate that TGF-beta1 increases transcription of the latent transforming growth factor-beta binding protein-2 ( LTBP-2) gene in cultured human fetal lung fibroblasts leading to a significant increase in LTBP-2 mRNA steady state level. The stability of LTBP-2 mRNA was not appreciably altered. A corresponding increase in production of LTBP-2 protein accompanied the increase in mRNA. Through the use of specific inhibitors, we demonstrate that a member of the Ras super family and a protein kinase C, probably of the atypical (non-diacylglycerol, non-Ca++ dependent) class are likely to be components in the signaling pathway. However, phospholipases, G proteins and extracellular-signal regulated kinases do not appear to be involved. These results combined with previous findings on elastin regulation by TGF-beta1 (Kucich et al. (1997). Am. J. Respir. Cell Mol. Biol., 17: 10-16) demonstrate that TGF-beta1 can coordinately increase the steady state levels of mRNAs encoding components of the elastic fiber, but through diverse mechanisms. In contrast to LTBP-2, increased elastin expression is achieved by message stabilization. Furthermore, the TGF-beta1 signaling pathways differ and while the pathway leading to increased LTBP-2 transcription shares components with those modulating transcription of other genes, it is unlikely to be precisely congruent with any other previously described one.
authors.affiliation: Department of Anatomy and Histology, University of Pennsylvania School of Dental Medicine, Philadelphia 19104, USA.
authors.forename: W
authors.initials: W
authors.lastname: Ahmed
authors.forename: U
authors.initials: U
authors.lastname: Kucich
authors.forename: W
authors.initials: W
authors.lastname: Abrams
authors.forename: M
authors.initials: M
authors.lastname: Bashir
authors.forename: J
authors.initials: J
authors.lastname: Rosenbloom
authors.forename: F
authors.initials: F
authors.lastname: Segade
authors.forename: R
authors.initials: R
authors.lastname: Mecham
authors.forename: J
authors.initials: J
authors.lastname: Rosenbloom
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D053779:Latent TGF-beta Binding Proteins; D009281:Naphthalenes / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012333:RNA, Messenger; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; C509035:LTBP2 protein, human; D053779:Latent TGF-beta Binding Proteins; D009281:Naphthalenes; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C061465:calphostin complex; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one