Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-β-like signaling pathway
Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-β-like signaling pathway
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DOI：
10.1172/jci35930
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发表时间：
2009-02-01
影响因子：
15.9
通讯作者：
Ye, Qinong
中科院分区：
文献类型：
--
作者：
Ding, Lihua;Wang, Zhaoyun;Ye, Qinong
4个半LIM （FHL）蛋白属于一个仅限LIM的蛋白家族，它调节细胞增殖、分化和凋亡。每种FHL蛋白在癌症发生和进展中的确切功能尚不清楚。在这里，我们报道了FHL1、FHL2和FHL3在物理和功能上与Smad2、Smad3和Smad4相互作用，Smad2、Smad3和Smad4是癌症发生和进展的重要调节因子，以tgf - β不依赖的方式相互作用。酪蛋白激酶18，而不是tgf - β受体，是fhl介导的tgf - β样反应所必需的，包括Smad2/3磷酸化的增加、Smad2/3和Smad4的相互作用、Smad蛋白的核积累、肿瘤抑制基因p21的激活和癌基因c-myc的抑制。FHL1-3抑制人肝癌细胞体外锚定依赖性和非依赖性生长和裸鼠肿瘤形成。对临床样本的进一步分析显示，FHL蛋白在肝细胞癌中经常下调，这与tgf - β样反应的降低有关。通过建立FHL蛋白和Smad蛋白之间的联系，本研究确定了我们认为是一种新的tgf - β样信号通路，并表明FHL蛋白可能是癌症治疗的有用分子靶点。
The four-and-a-half LIM (FHL) proteins belong to a family of LIM-only proteins that regulate cell proliferation, differentiation, and apoptosis. The exact functions of each FHL protein in cancer development and progression remain unknown. Here we report that FHL1, FHL2, and FHL3 physically and functionally interact with Smad2, Smad3, and Smad4, important regulators of cancer development and progression, in a TGF-beta-independent manner. Casein kinase 18, but not the TGF-beta receptor, was required for the FHL-mediated TGF-beta-like responses, including increased phosphorylation of Smad2/3, interaction of Smad2/3 and Smad4, nuclear accumulation of Smad proteins, activation of the tumor suppressor gene p21, and repression of the oncogene c-myc. FHL1-3 inhibited anchorage-dependent and -independent growth of a human hepatoma cell fine in vitro and tumor formation in nude mice. Further analysis of clinical samples revealed that FHL proteins are often downregulated in hepatocellular carcinomas and that this correlates with decreased TGF-beta-like responses. By establishing a link between FHL proteins and Smad proteins, this study identifies what we believe to be a novel TGF-beta-like signaling pathway and indicates that FHL proteins may be useful molecular targets for cancer therapy.