de Caestecker M P, Piek E, Roberts A B
Laboratory of Cell Regulation and Carcinogenesis, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-5055, USA.
J Natl Cancer Inst. 2000 Sep 6;92(17):1388-402. doi: 10.1093/jnci/92.17.1388.
Signaling from transforming growth factor-beta (TGF-beta) through its unique transmembrane receptor serine-threonine kinases plays a complex role in carcinogenesis, having both tumor suppressor and oncogenic activities. Tumor cells often escape from the antiproliferative effects of TGF-beta by mutational inactivation or dysregulated expression of components in its signaling pathway. Decreased receptor function and altered ratios of the TGF-beta type I and type II receptors found in many tumor cells compromise the tumor suppressor activities of TGF-beta and enable its oncogenic functions. Recent identification of a family of intracellular mediators, the Smads, has provided new paradigms for understanding mechanisms of subversion of TGF-beta signaling by tumor cells. In addition, several proteins recently have been identified that can modulate the Smad-signaling pathway and may also be targets for mutation in cancer. Other pathways such as various mitogen-activated protein kinase cascades also contribute substantially to TGF-beta signaling. Understanding the interplay between these signaling cascades as well as the complex patterns of cross-talk with other signaling pathways is an important area of investigation that will ultimately contribute to understanding of the bifunctional tumor suppressor/oncogene role of TGF-beta in carcinogenesis.
转化生长因子-β（TGF-β）通过其独特的跨膜受体丝氨酸 - 苏氨酸激酶发出信号，在肿瘤发生过程中发挥着复杂的作用，兼具肿瘤抑制和致癌活性。肿瘤细胞常常通过其信号通路中成分的突变失活或表达失调，逃避TGF-β的抗增殖作用。许多肿瘤细胞中发现的受体功能降低以及TGF-β I型和II型受体比例的改变，损害了TGF-β的肿瘤抑制活性，并使其具有致癌功能。最近对一类细胞内介质Smads的鉴定，为理解肿瘤细胞颠覆TGF-β信号传导机制提供了新的范例。此外，最近还鉴定出几种能够调节Smad信号通路的蛋白质，它们也可能是癌症中发生突变的靶点。其他途径，如各种丝裂原活化蛋白激酶级联反应，也在很大程度上参与TGF-β信号传导。了解这些信号级联之间的相互作用以及与其他信号通路的复杂串扰模式，是一个重要的研究领域，最终将有助于理解TGF-β在肿瘤发生中作为双功能肿瘤抑制因子/癌基因的作用。
