Sidle A, Palaty C, Dirks P, Wiggan O, Kiess M, Gill R M, Wong A K, Hamel P A
Department of Molecular and Cellular Pathology, University of Toronto, Ontario, Canada.
Crit Rev Biochem Mol Biol. 1996 Jun;31(3):237-71. doi: 10.3109/10409239609106585.
Genetic evidence from retinoblastoma patients and experiments describing the mechanism of cellular transformation by the DNA tumor viruses have defined a central role for the retinoblastoma protein (pRB) family of tumor suppressors in the normal regulation of the eukaryotic cell cycle. These proteins, pRB, p107, and p130, act in a cell cycle-dependent manner to regulate the activity of a number of important cellular transcription factors, such as the E2F-family, which in turn regulate expression of genes whose products are important for cell cycle progression. In addition, inhibition of E2F activity by the pRB family proteins is required for cell cycle exit after terminal differentiation or nutrient depletion. The loss of functional pRB, due to mutation of both RB1 alleles, results in deregulated E2F activity and a predisposition to specific malignancies. Similarly, inactivation of the pRB family by the transforming proteins of the DNA tumor viruses overcomes cellular quiescence and prevents terminal differentiation by blocking the interaction of pRB, p107, and p130 with the E2F proteins, leading to cell cycle progression and, ultimately, cellular transformation. Together these two lines of evidence implicate the pRB family of negative cell cycle regulators and the E2F family of transcription factors as central components in the cell cycle machinery.
来自视网膜母细胞瘤患者的遗传证据以及描述DNA肿瘤病毒细胞转化机制的实验，确定了视网膜母细胞瘤蛋白（pRB）家族肿瘤抑制因子在真核细胞周期正常调控中的核心作用。这些蛋白，即pRB、p107和p130，以细胞周期依赖性方式发挥作用，调节许多重要细胞转录因子的活性，如E2F家族，而E2F家族又反过来调节其产物对细胞周期进程至关重要的基因的表达。此外，在终末分化或营养耗竭后细胞周期退出时，pRB家族蛋白对E2F活性的抑制是必需的。由于RB1两个等位基因的突变导致功能性pRB缺失，会导致E2F活性失控，并易患特定恶性肿瘤。同样，DNA肿瘤病毒的转化蛋白使pRB家族失活，通过阻断pRB、p107和p130与E2F蛋白的相互作用，克服细胞静止状态并阻止终末分化，导致细胞周期进程，最终导致细胞转化。这两条证据共同表明，负性细胞周期调节因子pRB家族和转录因子E2F家族是细胞周期机制的核心组成部分。
