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Evidence for TGF‐ß1 and bleomycin intracellular signaling through autocrine regulation of Smad 3 binding to the proximal promoter of the Smad 7 gene

Both Bleomycin and TGF‐β1 increase the transcription of the COL1A1 gene. Bleomycin acts through TGF‐β1. Bleomycin stimulates the COL1A1 promoter through the distal TGF‐β response element by intracellular and extracellular signaling. As demonstrated in this manuscript, Bleomycin's intracellular signaling can be explained by a decrease of Smad 3 transcription factor binding to the SBE located in the proximal promoter of the inhibitory Smad 7 gene. This would result in TGF‐β1‐induced activated SMADS, which would result in more collagen. Bleomycin's extracellular signaling results from the secretion of more latent TGF‐β produced by lung fibroblasts and cleaved to active TGF‐β extracellularly. Since the TGF‐β genes are auto‐induced in human embryonic IMR‐90 lung fibroblasts, this study indicates an autocrine mechanism to maintain homeostasis in vivo for fibroblasts and other cell types, which produce TGF‐β1 to limit the fibrogenic response to TGF‐β1 and Bleomycin. J. Cell. Biochem. 97: 933–939, 2006. © 2005 Wiley‐Liss, Inc.