Activation of elastin transcription by transforming growth factor-β in human lung fibroblasts
Open Access
- 1 April 2007
- journal article
- Published by American Physiological Society in American Journal of Physiology-Lung Cellular and Molecular Physiology
- Vol. 292 (4), L944-L952
- https://doi.org/10.1152/ajplung.00184.2006
Abstract
Elastin synthesis is essential for lung development and postnatal maturation as well as for repair following injury. Using human embryonic lung fibroblasts that express undetectable levels of elastin as assessed by Northern analyses, we found that treatment with exogenous transforming growth factor-β (TGF-β) induced rapid and transient increases in levels of elastin heterogeneous nuclear RNA (hnRNA) followed by increases of elastin mRNA and protein expression. In fibroblasts derived from transgenic mice, TGF-β induced increases in the expression of a human elastin gene promoter fragment driving a chloramphenicol acetyl transferase reporter gene. The induction of elastin hnRNA and mRNA expression by TGF-β was abolished by pretreatments with TGF-β receptor I inhibitor, global transcription inhibitor actinomycin D, and partially blocked by addition of protein synthesis inhibitor cycloheximide, but was not affected by the p44/42 MAPK inhibitor U0126. Pretreatment with the p38 MAPK inhibitor SB-203580 also partially attenuated the levels of TGF-β-induced elastin mRNA but not its hnRNA. Western analysis indicated that TGF-β stimulated Akt phosphorylation. Inhibition of phosphatidylinositol 3-kinase and Akt phosphorylation by LY-294002 abolished TGF-β-induced increases in elastin hnRNA and mRNA expression. Treatment of lung fibroblasts with interleukin-1β or the histone deacetylase inhibitor trichostatin A inhibited TGF-β-induced elastin mRNA and hnRNA expression by a mechanism that involved inhibition of Akt phosphorylation. Downregulation of Akt2 but not Akt1 expression employing small interfering RNA duplexes blocked TGF-β-induced increases of elastin hnRNA and mRNA levels. Together, our results demonstrated that TGF-β activates elastin transcription that is dependent on phosphatidylinositol 3-kinase/Akt activity.Keywords
This publication has 64 references indexed in Scilit:
- Differential effects of histone deacetylase inhibitors on phorbol ester‐ and TGF‐β1 induced murine tissue inhibitor of metalloproteinases‐1 gene expressionThe FEBS Journal, 2005
- Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesiclesThe Journal of cell biology, 2005
- TGF‐β‐induced expression of tissue inhibitor of metalloproteinases‐3 gene in chondrocytes is mediated by extracellular signal‐regulated kinase pathway and Sp1 transcription factorJournal of Cellular Physiology, 2004
- Transforming growth factor beta stimulation of biglycan gene expression is potentially mediated by sp1 binding factorsJournal of Cellular Biochemistry, 2004
- Smad-dependent and Smad-independent pathways in TGF-β family signallingNature, 2003
- Mechanisms of TGF-β Signaling from Cell Membrane to the NucleusCell, 2003
- Loss of integrin αvβ6-mediated TGF-β activation causes Mmp12-dependent emphysemaNature, 2003
- Sp1 and Smad Proteins Cooperate to Mediate Transforming Growth Factor-β1-induced α2(I) Collagen Expression in Human Glomerular Mesangial CellsPublished by Elsevier BV ,2001
- Localization of elastin mRNA and TGF-β1 in rat aorta and caudal artery as a function of ageCell and tissue research, 1998
- Insulin-like Growth Factor-I Regulates Transcription of the Elastin Gene through a Putative Retinoblastoma Control ElementJournal of Biological Chemistry, 1996