Bandara L R, Adamczewski J P, Hunt T, La Thangue N B
Laboratory of Eukaryotic Molecular Genetics, MRC National Institute for Medical Research, Mill Hill, London, UK.
Nature. 1991 Jul 18;352(6332):249-51. doi: 10.1038/352249a0.
The retinoblastoma gene (Rb) product is a negative regulator of cellular proliferation, an effect that could be mediated in part at the transcriptional level through its ability to complex with the sequence-specific transcription factor DRTF1. This interaction is modulated by adenovirus E1a, which sequesters the Rb protein and several other cellular proteins, including cyclin A, a molecule that undergoes cyclical accumulation and destruction during each cell cycle and which is required for cell cycle progression. Cyclin A, which also complexes with DRTF1, facilitates the efficient assembly of the Rb protein into the complex. This suggests a role for cyclin A in regulating transcription and defines a transcription factor through which molecules that regulate the cell cycle in a negative fashion, such as Rb, and in a positive fashion, such as cyclin A, interact. Mutant loss-of-function Rb alleles, which occur in a variety of tumour cells, also fail to complex with E1a and large T antigen. Here we report on a naturally occurring loss-of-function Rb allele encoding a protein that fails to complex with DRTF1. This might explain how mutation in the Rb gene prevents negative growth control.
视网膜母细胞瘤基因（Rb）产物是细胞增殖的负调节因子，这种作用可能部分是通过其与序列特异性转录因子DRTF1形成复合物的能力在转录水平介导的。腺病毒E1a可调节这种相互作用，它能隔离Rb蛋白和其他几种细胞蛋白，包括细胞周期蛋白A，该分子在每个细胞周期中经历周期性积累和破坏，并且是细胞周期进程所必需的。细胞周期蛋白A也与DRTF1形成复合物，促进Rb蛋白高效组装到复合物中。这表明细胞周期蛋白A在调节转录中发挥作用，并定义了一种转录因子，通过该转录因子，以负向方式调节细胞周期的分子（如Rb）和以正向方式调节细胞周期的分子（如细胞周期蛋白A）相互作用。在多种肿瘤细胞中出现的突变失活Rb等位基因也无法与E1a和大T抗原形成复合物。在此，我们报道了一种天然存在的失活Rb等位基因，其编码的蛋白质无法与DRTF1形成复合物。这可能解释了Rb基因中的突变如何阻止负向生长控制。
