Kim S-J, Letterio J
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD 20892, USA.
Leukemia. 2003 Sep;17(9):1731-7. doi: 10.1038/sj.leu.2403069.
Transforming growth factor-beta (TGF-beta) is perhaps the most potent endogenous negative regulator of hematopoiesis. The intracellular signaling events mediating the effects of TGF-beta are multiple, involving extensive crosstalk between Smad-dependent and MAP-kinase-dependent pathways. We are only beginning to understand the importance of the balance between these cascades as a determinant of the response to TGF-beta, and have yet to determine the roles that disruption in TGF-beta signaling pathways might play in leukemogenesis. This review summarizes current knowledge regarding the function of TGF-beta in normal and malignant hematopoiesis. The principal observations made by gene targeting studies in mice are reviewed, with an emphasis on how a disruption of this pathway in vivo can affect blood cell development and immune homeostasis. We overview genetic alterations that lead to impaired TGF-beta signaling in hematopoietic neoplasms, including the suppression of Smad-dependent transcriptional responses by oncoproteins such as Tax and Evi-1, and fusion proteins such as AML1/ETO. We also consider mutations in genes encoding components of the core cell cycle machinery, such as p27(Kip1) and p15(INK4A), and emphasize their impact on the ability of TGF-beta to induce G1 arrest. The implications of these observations are discussed, and opinions regarding important directions for future research on TGF-beta in hematopoiesis are provided.
转化生长因子-β（TGF-β）可能是造血作用中最有效的内源性负调节因子。介导TGF-β作用的细胞内信号转导事件多种多样，涉及Smad依赖性途径和丝裂原活化蛋白激酶（MAP激酶）依赖性途径之间广泛的相互作用。我们才刚刚开始理解这些级联反应之间平衡作为TGF-β反应决定因素的重要性，并且尚未确定TGF-β信号通路的破坏在白血病发生过程中可能发挥的作用。这篇综述总结了关于TGF-β在正常和恶性造血作用中功能的当前知识。回顾了在小鼠中进行的基因靶向研究的主要观察结果，重点是该途径在体内的破坏如何影响血细胞发育和免疫稳态。我们概述了导致造血肿瘤中TGF-β信号受损的基因改变，包括癌蛋白如Tax和Evi-1以及融合蛋白如AML1/ETO对Smad依赖性转录反应的抑制。我们还考虑了编码核心细胞周期机制成分的基因中的突变，如p27（Kip1）和p15（INK4A），并强调它们对TGF-β诱导G1期停滞能力的影响。讨论了这些观察结果的意义，并提供了关于未来造血作用中TGF-β研究重要方向的观点。
