Nitric oxide-mediated upregulation of the TGF-β-inducible early response gene-1 (TIEG1) in human fibroblasts by mRNA stabilization independent of TGF-β

Nitric oxide serves various roles in mammalian cells, including intracellular signaling and cell killing. To recognize the dynamic molecular changes in response to NO, microarray analysis was applied to human fibroblasts (IMR-90) exposed to sublethal levels of NO. Among the > 300 transcripts induced by NO, we focused on the mRNA encoded by the transforming growth factor-β- (TGF-β-) inducible early response 1 gene (TIEG1), which plays a pivotal role in TGF-β-regulated cell growth control and apoptosis. Northern blotting analysis demonstrated that NO upregulates TIEG1 mRNA in a dose-dependent manner. Anti-TGF-β antibodies prevented TIEG1 mRNA induction by TGF-β, but not the induction by NO. Conversely, NO had no effect on the amounts of total TGF-β or its active form in culture supernatants. However, the half-life of the TIEG1 transcript was strongly increased (6-fold) upon exposure of the cells to NO. Thus, NO upregulates TIEG1 mRNA by stabilization independently of TGF-β. The TIEG1 mRNA now joins heme oxygenase-1 mRNA in displaying regulation by NO-mediated stabilization. It remains to be determined whether the same control mechanism operates on these and perhaps other messages.