Jooss K, Lam E W, Bybee A, Girling R, Müller R, La Thangue N B
Laboratory of Eukaryotic Molecular Genetics, MRC National Institute of Medical Research, Mill Hill, London.
Oncogene. 1995 Apr 20;10(8):1529-36.
The cellular transcription factor DRTF1/E2F is implicated in the control of cellular proliferation due to its interaction with key regulators of cell cycle progression, such as the retinoblastoma tumour suppressor gene product, cyclins and cyclin-dependent kinases. DRTF1/E2F is a heterodimeric DNA binding activity which arises when a member of two distinct families of proteins, DP and E2F, interact as DP/E2F heterodimers, for example, DP-1 and E2F-1. In DRTF1/E2F the activity of DP-1 is under cell cycle control, possibly by phosphorylation, and in many types of cells it is a frequent, if not general DNA binding component of DRTF1/E2F. The expression of other DP proteins, such as DP-2, is tissue-restricted. Here, we show that DP-1 and DP-2 are integrated with another growth regulating pathway which involves signal transduction emanating from activated Ras protein. Thus, activated Ha-ras can co-operate with DP-1 or DP-2 in the transformation of rat embryo fibroblasts, establishing for the first time that DP proteins are endowed with proto-oncogenic activity. Moreover, an analysis of a dominant-negative and mutant DP-1 proteins suggests that the primary target through which DP-1 mediates its oncogenic activity is unlikely to be due to the regulation of E2F site-transcription, suggesting an E2F-independent effector function for DP-1. These results therefore establish DP genes as proto-oncogenes and thus argue that deregulating the normal control of DP protein activity will be important in promoting aberrant cellular proliferation.
细胞转录因子DRTF1/E2F因其与细胞周期进程的关键调节因子相互作用而参与细胞增殖的调控，这些关键调节因子包括视网膜母细胞瘤抑癌基因产物、细胞周期蛋白和细胞周期蛋白依赖性激酶。DRTF1/E2F是一种异二聚体DNA结合活性，当两个不同蛋白质家族（DP和E2F）的成员以DP/E2F异二聚体形式相互作用时产生，例如DP-1和E2F-1。在DRTF1/E2F中，DP-1的活性受细胞周期控制，可能通过磷酸化实现，并且在许多类型的细胞中，它是DRTF1/E2F常见的（即便不是普遍的）DNA结合成分。其他DP蛋白，如DP-2的表达具有组织限制性。在此，我们表明DP-1和DP-2与另一条生长调节途径整合，该途径涉及由活化的Ras蛋白发出的信号转导。因此，活化的Ha-ras可与DP-1或DP-2协同作用，使大鼠胚胎成纤维细胞发生转化，首次证实DP蛋白具有原癌基因活性。此外，对显性负性和突变型DP-1蛋白的分析表明，DP-1介导其致癌活性的主要靶点不太可能是由于对E2F位点转录的调控，这表明DP-1具有不依赖E2F的效应器功能。因此，这些结果将DP基因确立为原癌基因，从而表明解除对DP蛋白活性的正常控制在促进异常细胞增殖中很重要。
