Kaelin W G
Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Ann N Y Acad Sci. 1997 Dec 29;833:29-33. doi: 10.1111/j.1749-6632.1997.tb48589.x.
Mutations involving the retinoblastoma tumor-suppressor gene (RB-1) have been described in a variety of human neoplasms. In addition, many tumors that retain a wild-type RB-1 allele harbor mutations that indirectly impair the function of the RB-1 gene product (pRB). pRB is a nuclear protein that regulates cell-cycle progression and, in at least certain tissues, differentiation. The former has been linked to its ability to form complexes with members of the E2F transcription factor family. E2F DNA-binding sites have been identified in the regulatory regions of a number of genes involved in cell-cycle progression. pRB-E2F complexes actively repress transcription when bound to these sites. All tumor-derived pRB mutants have lost the ability to bind to E2F. Conversely, activation of E2F-responsive genes is sufficient to overcome a pRB-induced cell-cycle block and, in certain cell types, can lead to transformation. Thus, E2F appears to be a physiologically relevant target of pRB action, and deregulation of E2F-responsive genes is a common, and possibly universal, step in human carcinogenesis.
在多种人类肿瘤中都已发现涉及视网膜母细胞瘤肿瘤抑制基因（RB - 1）的突变。此外，许多保留野生型RB - 1等位基因的肿瘤存在间接损害RB - 1基因产物（pRB）功能的突变。pRB是一种核蛋白，可调节细胞周期进程，并且在至少某些组织中还参与细胞分化。前者与它和E2F转录因子家族成员形成复合物的能力有关。在许多参与细胞周期进程的基因的调控区域中已鉴定出E2F DNA结合位点。当pRB - E2F复合物与这些位点结合时，会积极抑制转录。所有源自肿瘤的pRB突变体都失去了与E2F结合的能力。相反，E2F反应性基因的激活足以克服pRB诱导的细胞周期阻滞，并且在某些细胞类型中可导致细胞转化。因此，E2F似乎是pRB作用的生理相关靶点，E2F反应性基因的失调是人类致癌过程中常见且可能普遍的步骤。
