Transforming activity of Fbxo7 is mediated specifically through regulation of cyclin D/cdk6
Transforming activity of Fbxo7 is mediated specifically through regulation of cyclin D/cdk6
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DOI：
10.1038/sj.emboj.7600775
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发表时间：
2005-09-07
期刊：
影响因子：
11.4
通讯作者：
Boshoff, C
中科院分区：
文献类型：
--
作者：
Laman, H;Funes, JM;Boshoff, C
D周期蛋白（D1， D2和D3）及其催化亚基（周期蛋白依赖性激酶cdk4和cdk6）在细胞周期进入中起促进作用，但不是必需的作用。已经报道了d型细胞周期蛋白和cdks的组织特异性功能；然而，这些激酶的生化特性是难以区分的。我们报道了F box蛋白Fbxo7与细胞和病毒D细胞周期蛋白相互作用，并在体外和体内区分了与D型细胞周期蛋白结合的cdks，特别是与cdk6结合。Fbxo7特异性调节D cyclin/cdk6复合物：Fbxo7敲低降低了cdk6与cyclin的关联，其过表达增加了D cyclin/cdk6活性和E2F活性。Fbxo7与p27相互作用，但其对cyclin D/cdk6活性的增强与p21/p27无关。Fbxo7过表达转化小鼠成纤维细胞，使其在胸腺裸鼠中具有致瘤性。转化的表型依赖于cdk6，因为敲低cdk6可以逆转它们。Fbxo7在上皮肿瘤中高表达，但在正常组织中不表达，这表明它可能在人类癌症中具有原致癌作用。
D cyclins (D1, D2 and D3) and their catalytic subunits (cyclin-dependent kinases cdk4 and cdk6) have a facilitating, but nonessential, role in cell cycle entry. Tissue-specific functions for D-type cyclins and cdks have been reported; however, the biochemical properties of these kinases are indistinguishable. We report that an F box protein, Fbxo7, interacted with cellular and viral D cyclins and distinguished among the cdks that bind D-type cyclins, specifically binding cdk6, in vitro and in vivo. Fbxo7 specifically regulated D cyclin/cdk6 complexes: Fbxo7 knockdown decreased cdk6 association with cyclin and its overexpression increased D cyclin/cdk6 activity and E2F activity. Fbxo7 interacted with p27, but its enhancement of cyclin D/cdk6 activity was p21/p27 independent. Fbxo7 overexpression transformed murine fibroblasts, rendering them tumorigenic in athymic nude mice. Transformed phenotypes were dependent on cdk6, as knockdown of cdk6 reversed them. Fbxo7 was highly expressed in epithelial tumors, but not in normal tissues, suggesting that it may have a proto-oncogenic role in human cancers.