DNA tumor virus oncoproteins and retinoblastoma gene mutations share the ability to relieve the cell's requirement for cyclin D1 function in G1.
DNA tumor virus oncoproteins and retinoblastoma gene mutations share the ability to relieve the cell's requirement for cyclin D1 function in G1.
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DOI：
10.1083/jcb.125.3.625
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发表时间：
1994-05
期刊：
影响因子：
--
通讯作者：
Bartek J
中科院分区：
文献类型：
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作者：
Lukas J;Müller H;Bartkova J;Spitkovsky D;Kjerulff AA;Jansen-Dürr P;Strauss M;Bartek J
视网膜母细胞瘤基因产物（pRB）通过与包括潜在致癌细胞周期蛋白D1在内的多种细胞调控蛋白形成复合物，参与细胞分裂周期的调控。扩展目前关于pRB和d型细胞周期蛋白之间新出现的功能相互作用的观点，我们现在报道了pRB正调控细胞周期蛋白D1的表达。Cyclin D1 mRNA和蛋白在表达SV40大T抗原、腺病毒E1A和乳头瘤病毒E7/E6癌基因产物的细胞中特异性下调，这种作用需要完整的rb结合、E1A的CR2结构域。在基因rb缺陷细胞系中，细胞周期蛋白D1的表达也异常低，其中异位表达的野生型pRB导致特异性诱导这种G1周期蛋白。在功能水平上，抗体介导的细胞周期蛋白D1敲除实验表明，在pRB通过与T抗原、E1A或E7癌蛋白形成复合物而失活的细胞系中，以及在RB基因发生功能丧失突变的细胞中，G1进展通常需要的细胞周期蛋白D1对于细胞周期的传代是必不可少的。在RB突变的细胞中，细胞周期蛋白D1表达的实验升高并没有恢复对细胞周期蛋白D1功能的需求，而将野生型RB重新引入RB缺陷细胞可恢复细胞周期蛋白D1检查点。这些结果强烈提示pRB是cyclin D1的主要靶点，在缺乏功能性RB的细胞中，pRB的细胞周期调节功能变得不可或缺。基于包括本研究在内的现有数据，我们提出了一个自我调节反馈回路机制模型，该机制可以调节cyclin D1基因的表达和pRB的活性，从而有助于循环哺乳动物细胞的G1期检查点控制。
The retinoblastoma gene product (pRB) participates in the regulation of the cell division cycle through complex formation with numerous cellular regulatory proteins including the potentially oncogenic cyclin D1. Extending the current view of the emerging functional interplay between pRB and D-type cyclins, we now report that cyclin D1 expression is positively regulated by pRB. Cyclin D1 mRNA and protein is specifically downregulated in cells expressing SV40 large T antigen, adenovirus E1A, and papillomavirus E7/E6 oncogene products and this effect requires intact RB-binding, CR2 domain of E1A. Exceptionally low expression of cyclin D1 is also seen in genetically RB-deficient cell lines, in which ectopically expressed wild-type pRB results in specific induction of this G1 cyclin. At the functional level, antibody-mediated cyclin D1 knockout experiments demonstrate that the cyclin D1 protein, normally required for G1 progression, is dispensable for passage through the cell cycle in cell lines whose pRB is inactivated through complex formation with T antigen, E1A, or E7 oncoproteins as well as in cells which have suffered loss-of-function mutations of the RB gene. The requirement for cyclin D1 function is not regained upon experimental elevation of cyclin D1 expression in cells with mutant RB, while reintroduction of wild-type RB into RB-deficient cells leads to restoration of the cyclin D1 checkpoint. These results strongly suggest that pRB serves as a major target of cyclin D1 whose cell cycle regulatory function becomes dispensable in cells lacking functional RB. Based on available data including this study, we propose a model for an autoregulatory feedback loop mechanism that regulates both the expression of the cyclin D1 gene and the activity of pRB, thereby contributing to a G1 phase checkpoint control in cycling mammalian cells.