Johnson D G
Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville 78957, USA.
Oncogene. 1995 Nov 2;11(9):1685-92.
Previous experiments have demonstrated that the regulation of E2F-1 transcription factor activity is critical for the maintenance of normal cell proliferation control. Regulation of E2F-1 is accomplished through at least two mechanisms: posttranslational regulation by binding proteins such as Rb and transcriptional regulation of the E2F-1 gene. The E2F-1 gene promoter has recently been isolated to examine this latter aspect of E2F-1 regulation. Preliminary studies demonstrate that the E2F-1 promoter is under E2F-dependent negative control during the cell growth response, being transcriptionally repressed through E2F sites in G0 and early G1. We now demonstrate that the presence of an E2F DNA-binding complex containing the Rb-related p130 protein (Rb2) correlates with E2F-1 gene repression and that overexpression of p130 inhibits transcription from the E2F-1 promoter. Moreover, D-type cyclin-dependent kinase activity specifically activates the E2F-1 promoter by relieving E2F-mediated repression but is inhibited by coexpression of the cdk4 and cdk6 inhibitor p16 (CDKN2, MTS1, INK4). Taken together, these findings suggest that E2F-1 gene expression is controlled during cell cycle progression by a regulatory network involving at least one oncogene (cyclin D1) and several potential tumor suppressor genes.
先前的实验表明，E2F-1转录因子活性的调节对于维持正常细胞增殖控制至关重要。E2F-1的调节至少通过两种机制实现：通过与Rb等结合蛋白进行翻译后调节以及对E2F-1基因的转录调节。最近分离出了E2F-1基因启动子，以研究E2F-1调节的后一个方面。初步研究表明，在细胞生长反应过程中，E2F-1启动子处于E2F依赖性负调控之下，在G0期和G1早期通过E2F位点被转录抑制。我们现在证明，含有与Rb相关的p130蛋白（Rb2）的E2F DNA结合复合物的存在与E2F-1基因抑制相关，并且p130的过表达抑制E2F-1启动子的转录。此外，D型细胞周期蛋白依赖性激酶活性通过解除E2F介导的抑制作用特异性激活E2F-1启动子，但被cdk4和cdk6抑制剂p16（CDKN2、MTS1、INK4）的共表达所抑制。综上所述，这些发现表明，在细胞周期进程中，E2F-1基因表达受一个调控网络控制，该网络至少涉及一种癌基因（细胞周期蛋白D1）和几种潜在的肿瘤抑制基因。
