Genomic locus and promoter region of rat Smad7, an important antagonist ofTGF beta signaling

SMAD proteins are essential components of the intracellular signaling pathw ays utilized by members of the transforming growth factor beta (TGF beta) s uperfamily of growth factors. Certain SMAD proteins (Smad1, 2, 3, and 5) ca n act as regulated transcriptional activators. This process involves phosph orylation of these proteins by activated TGF beta receptors. Recently, Smad 6 and Smad7 were identified; they antagonize TGF beta signaling by preventi ng the activation of signal-transducing SMAD complexes. TGF beta rapidly in duces the expression of Smad7 mRNA, suggesting participation of Smad7 in a negative feedback loop to control TGF beta responses. Similarly, epidermal growth factor (EGF) and interferon gamma (IFN gamma) have been reported to induce Smad7 expression. In a rat model system of liver fibrosis, TGF beta inducibility of Smad7 is abrogated during transformation of hepatic stellat e cells (HSC), indicating an important switch in transcriptional regulation of the gene. With the detailed characterization of the rat Smad7 genomic o rganization including the promoter region, we present the first identified Smad7 gene so far. The gene is composed of four exons separated by three in trons covering a DNA region of about 30 kilobases (kb) in total. The major transcription start site is conserved between rat and mouse, and two polyad enylation signals were detected. In the promoter region, a potential CAGA b ox, a signal transducer and activator of transcription (STAT) factor-relate d recognition site, and different AP1 sites were identified, which could be the targets of TGF beta, IFN gamma, and EGF-dependent Smad7 transcription initiation.