基因君官网2014年1月8日讯 /生物谷BIOON/ –TGF-β在癌症生物学中一直是个秘密，TGF-β如何既可以阻止癌细胞的形成，又如何刺激肿瘤积极生长。
现在，美国密歇根州综合癌症中心的研究人员已经发现一个关键基因，可以解释这种矛盾，提供潜在治疗靶标。
TGF-β是已知的肿瘤抑制因子，这意味着对于保持细胞正常生长是必要的。但在某些时候，它的功能会转换成肿瘤启动子，促进癌症发展与扩散。研究人员发现BUB1可作为参与调节TGF-β受体的一个关键基因。
这项研究发表在Science Signaling杂志上。
BUB1是众所周知的在细胞分裂中发挥作用。但是，这是首次将Bub1与TGF-beta联系起来。我们认为，这也许可以解释TGF-β作为肿瘤启动子和抑癌因子的悖论。
密歇根大学研究人员包括Shyam Nyati博士团队开发出一种方法筛选调节TGF-β受体的基因。当对肺癌和乳腺癌细胞的人类基因组720个基因进行了筛选，BUB1发挥对TGF-β信号调控的强烈作用。
BUB1显示能结合到TGF-β受体，并允许开启侵袭性细胞的生长。当研究人员阻断BUB1，它彻底关闭TGF-β途径。TGF-β已知在侵袭性癌细胞发展中有作用，研究人员也已知道，BUB1在许多不同类型的癌症中高度表达。
因为BUB1在许多类型癌症中表达，因此靶向它开发出一种药物发现可能潜在地影响多种癌症。目前已开发出靶向BUB1的化合物，但还没有准备好在患者中开展测试。初始实验室测试表明，这种BUB1的抑制剂可以非常特异性靶向BUB1，而不会损坏细胞的其他部分。（生物谷Bioon.com）
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The kinase activity of the Ser/Thr kinase BUB1 promotes TGF-β signaling
Shyam Nyati,et al.
Transforming growth factor–β (TGF-β) signaling regulates cell proliferation and differentiation, which contributes to development and disease. Upon binding TGF-β, the type I receptor (TGFBRI) binds TGFBRII, leading to the activation of the transcription factors SMAD2 and SMAD3. Using an RNA interference screen of the human kinome and a live-cell reporter for TGFBR activity, we identified the kinase BUB1 (budding uninhibited by benzimidazoles-1) as a key mediator of TGF-β signaling. BUB1 interacted with TGFBRI in the presence of TGF-β and promoted the heterodimerization of TGFBRI and TGFBRII. Additionally, BUB1 interacted with TGFBRII, suggesting the formation of a ternary complex. Knocking down BUB1 prevented the recruitment of SMAD3 to the receptor complex, the phosphorylation of SMAD2 and SMAD3 and their interaction with SMAD4, SMAD-dependent transcription, and TGF-β–mediated changes in cellular phenotype including epithelial-mesenchymal transition (EMT), migration, and invasion. Knockdown of BUB1 also impaired noncanonical TGF-β signaling mediated by the kinases AKT and p38 MAPK (mitogen-activated protein kinase). The ability of BUB1 to promote TGF-β signaling depended on the kinase activity of BUB1. A small-molecule inhibitor of the kinase activity of BUB1 (2OH-BNPP1) and a kinase-deficient mutant of BUB1 suppressed TGF-β signaling and formation of the ternary complex in various normal and cancer cell lines. 2OH-BNPP1 administration to mice bearing lung carcinoma xenografts reduced the amount of phosphorylated SMAD2 in tumor tissue. These findings indicated that BUB1 functions as a kinase in the TGF-β pathway in a role beyond its established function in cell cycle regulation and chromosome cohesion.