Transforming growth factor-β adaptor, β2-spectrin, modulates cyclin dependent kinase 4 to reduce development of hepatocellular cancer.
Transforming growth factor-β adaptor, β2-spectrin, modulates cyclin dependent kinase 4 to reduce development of hepatocellular cancer.
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DOI：
10.1002/hep.24128
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发表时间：
2011-05
期刊：
影响因子：
13.5
通讯作者：
Mishra, Lopa
中科院分区：
文献类型：
--
作者：
Baek, Hye Jung;Pishvaian, Michael J.;Tang, Yi;Kim, Tae Hyun;Yang, Shaoxian;El Zouhairi, Majed;Mendelson, Jon;Shetty, Kirti;Kallakury, Bhaskar;Berry, Deborah L.;Shin, Kyung Hwan;Mishra, Bibhuti;Reddy, E. Premkumar;Kim, Sang Soo;Mishra, Lopa
转化生长因子β (TGF-β)是细胞生长的重要调节因子，TGF-β信号的缺失是癌变的标志。Smad3/4接头蛋白β2-谱蛋白（β2SP）通过调节TGF-β的肿瘤抑制功能而成为肿瘤发生的有效调节剂。然而，迄今为止，TGF-β信号通路在肝细胞癌（HCC）发展的特定阶段的作用，特别是与其他致癌途径的激活有关的作用仍然知之甚少。在这里，我们确定了一个机制，通过β2SP，一个关键的Smad3接头，调节CDK4，细胞周期进程，并抑制HCC。β2SP的表达增加抑制视网膜母细胞瘤基因产物（Rb）的磷酸化，显著降低CDK4的表达，其程度远远大于其他CDKs和细胞周期蛋白。此外，β2SP抑制CDK4可有效恢复Rb低磷酸化和G1期细胞周期阻滞。我们进一步证明β2SP与CDK4和Smad3以竞争和TGF-β依赖的方式相互作用。此外，与β2sp+/−小鼠相比，β2sp+/−小鼠中cdk4的单倍不足导致HCC形成的急剧下降。因此，β2SP缺乏导致CDK4活化，并导致细胞周期失调、细胞增殖、癌基因过表达和hcc的形成。我们的数据突出了CDK4作为HCC药物抑制的一个有吸引力的靶点，并证明了β2sp+/−小鼠作为HCC治疗临床前疗效模型的重要性。
Transforming growth factor beta (TGF-β) is an important regulator of cell growth, and loss of TGF-β signaling is a hallmark of carcinogenesis. The Smad3/4 adaptor protein β2-spectrin (β2SP) is emerging as a potent regulator of tumorigenesis through its ability to modulate the tumor suppressor function of TGF-β. However, to date the role of the TGF-β signaling pathway at specific stages of the development of hepatocellular carcinoma (HCC), particularly in relation to the activation of other oncogenic pathways remains poorly delineated. Here, we identify a mechanism by which β2SP, a crucial Smad3 adaptor, modulates CDK4, cell cycle progression, and suppression of HCC. Increased expression of β2SP inhibits phosphorylation of the retinoblastoma gene product (Rb) and markedly reduces CDK4 expression to a far greater extent than other CDKs and cyclins. Furthermore, suppression of CDK4 by β2SP efficiently restores Rb hypophosphorylation and cell cycle arrest in G1. We further demonstrate that β2SP interacts with CDK4 and Smad3 in a competitive and TGF-β-dependent manner. In addition, haploinsufficiency of cdk4 in β2sp+/− mice results in a dramatic decline in HCC formation compared to that observed in β2sp+/− mice. Thus, β2SP deficiency leads to CDK4 activation and contributes to dysregulation of the cell cycle, cellular proliferation, oncogene overexpression, and the formation of HCCs. Our data highlight CDK4 as an attractive target for the pharmacologic inhibition of HCC and demonstrate the importance of β2sp+/− mice as a model of pre-clinical efficacy in the treatment of HCC.
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DOI：
10.1016/j.bbrc.2006.03.236
发表时间：
2006-06-16
影响因子：
3.1
作者：
Kim, Sang Soo;Shetty, Kirti;Mishra, Lopa
通讯作者：
Mishra, Lopa
影响因子：
30.8
作者：
Rane, SG;Dubus, P;Barbacid, M
通讯作者：
Barbacid, M
DOI：
10.1073/pnas.98.3.992
发表时间：
2001-01-30
影响因子：
11.1
作者：
Chen, CR;Kang, YB;Massagué, J
通讯作者：
Massagué, J
影响因子：
13.5
作者：
Ito, Y;Matsuura, N;Monden, M
通讯作者：
Monden, M
影响因子：
8
作者：
Kitisin, K.;Ganesan, N.;Mishra, L.
通讯作者：
Mishra, L.