Ki-67 serves as a prominent cancer marker. We describe how expression of the MKI67 gene coding for Ki-67 is controlled during the cell cycle. MKI67 mRNA and Ki-67 protein are maximally expressed in G₂ phase and mitosis. Expression is dependent on two CHR elements and one CDE site in the MKI67 promoter. DREAM transcriptional repressor complexes bind to both CHR sites and downregulate the expression in G₀/G₁ cells. Upregulation of MKI67 transcription coincides with binding of B-MYB-MuvB and FOXM1-MuvB complexes from S phase into G₂/M. Importantly, binding of B-MYB to the two CHR elements correlates with loss of CHR-dependent MKI67 promoter activation in B-MYB-knockdown experiments. In knockout cell models, we find that DREAM/MuvB-dependent transcriptional control cooperates with the RB Retinoblastoma tumor suppressor. Furthermore, the p53 tumor suppressor indirectly downregulates transcription of the MKI67 gene. This repression by p53 requires p21/CDKN1A. These results are consistent with a model in which DREAM, B-MYB-MuvB, and FOXM1-MuvB together with RB cooperate in cell cycle-dependent transcription and in transcriptional repression following p53 activation. In conclusion, we present mechanisms how MKI67 gene expression followed by Ki-67 protein synthesis is controlled during the cell cycle and upon induction of DNA damage, as well as upon p53 activation.

Ki-67 是一种重要的癌症标志物。我们描述了在细胞周期中如何控制编码 Ki-67的MKI67基因的表达。MKI67 mRNA 和Ki-67 蛋白在G ₂期和有丝分裂中表达最多。表达依赖于MKI67启动子中的两个 CHR 元件和一个 CDE 位点。DREAM 转录抑制复合物结合两个 CHR 位点并下调 G ₀ /G ₁细胞中的表达。MKI67转录的上调与 B-MYB-MuvB 和 FOXM1-MuvB 复合物从 S 期到 G ₂ /M 期的结合一致。重要的是，B-MYB 与两个 CHR 元件的结合与 CHR 依赖性缺失相关B-MYB 敲除实验中的MKI67启动子激活。在敲除细胞模型中，我们发现 DREAM/MuvB 依赖性转录控制与 RB 视网膜母细胞瘤肿瘤抑制因子协同作用。此外，p53 肿瘤抑制因子间接下调MKI67基因的转录。p53 的这种抑制需要 p21/CDKN1A。这些结果与 DREAM、B-MYB-MuvB 和 FOXM1-MuvB 以及 RB 在细胞周期依赖性转录和 p53 激活后的转录抑制中协同作用的模型一致。总之，我们介绍了在细胞周期和诱导 DNA 损伤以及 p53 激活时如何控制 MKI67基因表达和 Ki-67 蛋白合成的机制。