Schulze A, Zerfass K, Spitkovsky D, Henglein B, Jansen-Dürr P
Deutsches Krebsforschungszentrum, Forschungsschwerpunkt Angewandte Tumorvirologie, Heidelberg, Germany.
Oncogene. 1994 Dec;9(12):3475-82.
The oncoprotein cyclin D1 binds to and activates cyclin-dependent kinase 4 (cdk4), whose activity is inhibited by p16INK4, the product of the putative tumor suppressor gene MTS1. Cyclin D1 controls the timing of S phase onset in mammalian cells. We show that cyclin D1 acts as a positive regulator of the transcription factor E2F. In particular, cyclin D1 overexpression leads to the activation of the dihydrofolate reductase (DHFR) gene promoter. Activation depends on the E2F binding site in the DHFR promoter, known to mediate its activation at the G1/S transition in vivo. Cyclin D1 can also activate the adenovirus E2 promoter via E2F. Both promoters are repressed by p16INK4 and this repression can be released by overexpression of cdk4. The data reported here support a direct role for cyclin D1 and its associated kinase in cell cycle regulation of E2F activity and S phase-specific gene expression. In addition, we show that both E2F sites bind complexes containing the retinoblastoma protein (pRB) and that in RB-deficient cell lines overexpression of cyclin D1 fails to activate E2F-dependent transcription, indicating that pRB may be involved in promoter activation.
癌蛋白细胞周期蛋白D1与细胞周期蛋白依赖性激酶4（cdk4）结合并激活它，而cdk4的活性受假定的肿瘤抑制基因MTS1的产物p16INK4抑制。细胞周期蛋白D1控制哺乳动物细胞中S期起始的时间。我们发现细胞周期蛋白D1作为转录因子E2F的正向调节因子发挥作用。具体而言，细胞周期蛋白D1的过表达导致二氢叶酸还原酶（DHFR）基因启动子的激活。激活依赖于DHFR启动子中的E2F结合位点，已知该位点在体内介导其在G1/S期转换时的激活。细胞周期蛋白D1还可通过E2F激活腺病毒E2启动子。这两个启动子均受p16INK4抑制，且这种抑制可通过cdk4的过表达来解除。此处报道的数据支持细胞周期蛋白D1及其相关激酶在E2F活性的细胞周期调节和S期特异性基因表达中发挥直接作用。此外，我们发现两个E2F位点均结合含有视网膜母细胞瘤蛋白（pRB）的复合物，并且在RB缺陷细胞系中，细胞周期蛋白D1的过表达未能激活E2F依赖性转录，这表明pRB可能参与启动子激活。
