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Activation of elastin transcription by transforming growth factor- in human lung fibroblasts

Pulmonary Center and Department of Biochemistry at Boston University School of Medicine, and the Boston Veterans Affairs Healthcare System, Boston, Massachusetts

Submitted 19 May 2006 ; accepted in final form 27 December 2006

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- (TGF-) 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- 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- was abolished by pretreatments with TGF- 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--induced elastin mRNA but not its hnRNA. Western analysis indicated that TGF- stimulated Akt phosphorylation. Inhibition of phosphatidylinositol 3-kinase and Akt phosphorylation by LY-294002 abolished TGF--induced increases in elastin hnRNA and mRNA expression. Treatment of lung fibroblasts with interleukin-1 or the histone deacetylase inhibitor trichostatin A inhibited TGF--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--induced increases of elastin hnRNA and mRNA levels. Together, our results demonstrated that TGF- activates elastin transcription that is dependent on phosphatidylinositol 3-kinase/Akt activity.

heterogeneous nuclear RNA; emphysema; small interfering RNA; phosphatidylinositol 3-kinase/Akt

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