Rodgarkia-Dara Chantal, Vejda Susanne, Erlach Natascha, Losert Annemarie, Bursch Wilfried, Berger Walter, Schulte-Hermann Rolf, Grusch Michael
Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
Mutat Res. 2006 Nov-Dec;613(2-3):123-37. doi: 10.1016/j.mrrev.2006.07.002. Epub 2006 Sep 25.
Activins are a closely related subgroup within the TGFbeta superfamily of growth and differentiation factors. They consist of two disulfide-linked beta subunits. Four mammalian activin beta subunits termed beta(A), beta(B), beta(C), and beta(E), respectively, have been identified. Activin A, the homodimer of two beta(A) subunits, has important regulatory functions in reproductive biology, embryonic development, inflammation, and tissue repair. Several intra- and extracellular antagonists, including the activin-binding proteins follistatin and follistatin-related protein, serve to fine-tune activin A activity. In the liver there is compelling evidence that activin A is involved in the regulation of cell number by inhibition of hepatocyte replication and induction of apoptosis. In addition, activin A stimulates extracellular matrix production in hepatic stellate cells and tubulogenesis of sinusoidal endothelial cells, and thus contributes to restoration of tissue architecture during liver regeneration. Accumulating evidence from animal models and from patient data suggests that deregulation of activin A signaling contributes to pathologic conditions such as hepatic inflammation and fibrosis, acute liver failure, and development of liver cancer. Increased production of activin A was suggested to be a contributing factor to impaired hepatocyte regeneration in acute liver failure and to overproduction of extracellular matrix in liver fibrosis. Recent evidence suggests that escape of (pre)neoplastic hepatocytes from growth control by activin A through overexpression of follistatin and reduced activin production contributes to hepatocarcinogenesis. The role of the activin subunits beta(C) and beta(E), which are both highly expressed in hepatocytes, is still quite incompletely understood. Down-regulation in liver tumors and a growth inhibitory function similar to that of beta(A) has been shown for beta(E). Contradictory results with regard to cell proliferation have been reported for beta(C). The profound involvement of the activin axis in liver biology and in the pathogenesis of severe hepatic diseases suggests activin as potential target for therapeutic interventions.
激活素是生长和分化因子TGFβ超家族中密切相关的一个亚组。它们由两个通过二硫键连接的β亚基组成。已鉴定出四种哺乳动物激活素β亚基，分别称为β(A)、β(B)、β(C)和β(E)。激活素A是两个β(A)亚基的同二聚体，在生殖生物学、胚胎发育、炎症和组织修复中具有重要的调节功能。几种细胞内和细胞外拮抗剂，包括激活素结合蛋白卵泡抑素和卵泡抑素相关蛋白，可用于微调激活素A的活性。在肝脏中，有确凿证据表明激活素A通过抑制肝细胞复制和诱导凋亡参与细胞数量的调节。此外，激活素A刺激肝星状细胞中细胞外基质的产生以及窦状内皮细胞的管状生成，从而有助于肝脏再生过程中组织结构的恢复。来自动物模型和患者数据的越来越多的证据表明，激活素A信号传导失调会导致诸如肝炎症和纤维化、急性肝衰竭以及肝癌发生等病理状况。激活素A产生增加被认为是急性肝衰竭中肝细胞再生受损以及肝纤维化中细胞外基质过度产生的一个促成因素。最近的证据表明，（癌）前肝细胞通过卵泡抑素的过表达和激活素产生减少而逃避激活素A的生长控制，这有助于肝癌的发生。激活素亚基β(C)和β(E)在肝细胞中均高度表达，其作用仍未完全了解。已显示β(E)在肝肿瘤中下调并且具有与β(A)类似的生长抑制功能。关于β(C)，已报道了关于细胞增殖的矛盾结果。激活素轴在肝脏生物学和严重肝病发病机制中的深入参与表明激活素是治疗干预的潜在靶点。
