Roberts Anita B, Russo Angelo, Felici Angelina, Flanders Kathleen C
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20895-5055, USA.
Ann N Y Acad Sci. 2003 May;995:1-10. doi: 10.1111/j.1749-6632.2003.tb03205.x.
Transforming growth factor-beta (TGF-beta), a key player in a large variety of physiological and disease processes, signals through transmembrane receptor serine/threonine kinases to activate novel signaling intermediates called Smad proteins, which then modulate transcription of target genes. We have utilized mice with a targeted deletion of Smad3, one of two homologous proteins involved in signaling from TGF-beta/activin, to investigate the function of this particular pathway in transducing such effects of TGF-beta. The dramatic results of the absence of Smad3 on parameters of healing of cutaneous wounds, such as reepithelialization and influx of inflammatory cells, as well as on fibrosis as modeled by radiation fibrosis of skin in mice, suggest that signaling flux through Smad3 is critical for chemotactic activity of TGF-beta, inhibitory effects of TGF-beta on keratinocyte proliferation and migration, and chemoattraction and elaboration of extracellular matrix by fibroblasts in fibrotic diseases. We recently identified a novel molecule, TLP for TRAP-1-like protein, which selectively interferes with Smad3 signaling, and are currently investigating whether levels of this protein might be altered in disease to change the relative flow of information from Smad2 and Smad3.
转化生长因子-β（TGF-β）是多种生理和疾病过程中的关键因子，它通过跨膜受体丝氨酸/苏氨酸激酶发出信号，激活名为Smad蛋白的新型信号中间体，进而调节靶基因的转录。我们利用对Smad3进行靶向缺失的小鼠（Smad3是参与TGF-β/激活素信号传导的两种同源蛋白之一），来研究这一特定信号通路在转导TGF-β此类效应中的功能。Smad3缺失对皮肤伤口愈合参数（如再上皮化和炎症细胞流入）以及对小鼠皮肤放射性纤维化所模拟的纤维化的显著影响表明，通过Smad3的信号通量对于TGF-β的趋化活性、TGF-β对角质形成细胞增殖和迁移的抑制作用以及成纤维细胞在纤维化疾病中对细胞外基质的化学吸引和分泌至关重要。我们最近鉴定出一种新型分子，即TRAP-1样蛋白的TLP，它能选择性干扰Smad3信号传导，目前正在研究该蛋白水平在疾病中是否会发生改变，以改变来自Smad2和Smad3的相对信息流。
