Department of Molecular Oncology, Medical School, University of Leipzig, Leipzig, Germany.
Cell Cycle. 2012 Dec 15;11(24):4661-72. doi: 10.4161/cc.22917. Epub 2012 Nov 27.
The tumor suppressor p53 plays an important role in cell cycle arrest by downregulating transcription. Many genes repressed by p53 code for proteins with functions in G₂/M. A large portion of these genes is controlled by cell cycle-dependent elements (CDE) and cell cycle genes homology regions (CHR) in their promoters. Cyclin B2 is an example of such a gene, with a function at the transition from G₂ to mitosis. We find that p53-dependent downregulation of cyclin B2 promoter activity is dependent on an intact CHR element. In the presence of high levels of p53 or p21(WAF1/CIP1), protein binding to the CHR switches from MMB to DREAM complex by shifting MuvB core-associated proteins from B-Myb to E2F4/DP1/p130. The results suggest a model for p53-dependent transcriptional repression by which p53 directly activates p21(WAF1/CIP1). The inhibitor then prevents further phosphorylation of p130 by cyclin-dependent kinases. The presence of hypophosphorylated pocket proteins shifts the equilibrium for complex formation from MMB to DREAM. In the case of promoters that do not hold CDE or E2F elements, binding of DREAM and MMB solely relies on a CHR site. Thus, p53 can repress target genes indirectly through CHR elements.
肿瘤抑制因子 p53 通过下调转录在细胞周期停滞中发挥重要作用。许多受 p53 抑制的基因编码在 G₂/M 中具有功能的蛋白质。这些基因的很大一部分受细胞周期依赖性元件 (CDE) 和细胞周期基因同源区 (CHR) 在其启动子中的控制。细胞周期蛋白 B2 就是这样一个基因的例子，它在从 G₂ 到有丝分裂的过渡中具有功能。我们发现，p53 依赖性下调细胞周期蛋白 B2 启动子活性依赖于完整的 CHR 元件。在高水平的 p53 或 p21(WAF1/CIP1)存在下，通过将 MuvB 核心相关蛋白从 B-Myb 转移到 E2F4/DP1/p130，与 CHR 的蛋白结合从 MMB 切换到 DREAM 复合物。结果表明，p53 依赖的转录抑制模型，其中 p53 直接激活 p21(WAF1/CIP1)。抑制剂然后阻止 cyclin 依赖性激酶进一步磷酸化 p130。低磷酸化口袋蛋白的存在将复合物形成的平衡从 MMB 转移到 DREAM。对于不含有 CDE 或 E2F 元件的启动子，DREAM 和 MMB 的结合仅依赖于 CHR 位点。因此，p53 可以通过 CHR 元件间接抑制靶基因。
