Cutroneo Kenneth R
Department of Biochemistry, College of Medicine, 89 Beaumont Avenue, University of Vermont, Burlington, Vermont 05405, USA.
J Cell Biochem. 2006 Apr 1;97(5):933-9. doi: 10.1002/jcb.20594.
Both Bleomycin and TGF-beta1 increase the transcription of the COL1A1 gene. Bleomycin acts through TGF-beta1. Bleomycin stimulates the COL1A1 promoter through the distal TGF-beta 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-beta1-induced activated SMADS, which would result in more collagen. Bleomycin's extracellular signaling results from the secretion of more latent TGF-beta produced by lung fibroblasts and cleaved to active TGF-beta extracellularly. Since the TGF-beta 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-beta1 to limit the fibrogenic response to TGF-beta1 and Bleomycin.
博来霉素和转化生长因子β1（TGF-β1）均能增加COL1A1基因的转录。博来霉素通过TGF-β1发挥作用。博来霉素通过细胞内和细胞外信号传导，经远端TGF-β反应元件刺激COL1A1启动子。如本手稿所示，博来霉素的细胞内信号传导可通过Smad 3转录因子与位于抑制性Smad 7基因近端启动子中的SBE结合减少来解释。这将导致TGF-β1诱导的活化SMADs，进而产生更多胶原蛋白。博来霉素的细胞外信号传导源于肺成纤维细胞分泌更多的潜伏性TGF-β，并在细胞外裂解为活性TGF-β。由于TGF-β基因在人胚胎IMR-90肺成纤维细胞中是自动诱导的，本研究表明存在一种自分泌机制，以在体内维持成纤维细胞和其他产生TGF-β1的细胞类型的稳态，从而限制对TGF-β1和博来霉素的纤维化反应。
