The retinoblastoma protein RB and the transcription factor p53 are central tumor suppressors. They are often found inactivated in various tumor types. Both proteins play central roles in regulating the cell division cycle. RB forms complexes with the E2F family of transcription factors and downregulates numerous genes. Among the RB-E2F target genes, a large number code for key cell cycle regulators. Their transcriptional repression by the RB-E2F complex is released through phosphorylation of RB, leading to expression of the cell cycle regulators. The release from repression can be prevented by the cyclin-dependent kinase inhibitor p21/CDKN1A. The CDKN1A gene is transcriptionally activated by p53. Taken together, these elements constitute the p53-p21-RB signaling pathway. Following activation of p53, for example by viral infection or induction of DNA damage, p21 expression is upregulated. High levels of p21 then result in RB-E2F complex formation and downregulation of a large number of cell cycle genes. Thus, p53-dependent transcriptional repression is indirect. The reduced expression of the many regulators leads to cell cycle arrest. Examination of the p53-p21-RB targets and genes controlled by the related p53-p21-DREAM signaling pathway reveals that there is a large overlap of the two groups. Mechanistically this can be explained by replacing RB-E2F complexes with the DREAM transcriptional repressor complex at E2F sites in target promoters. In contrast to RB-E2F, DREAM can downregulate genes also through CHR transcription factor binding sites. This results in a distinct gene set controlled by p53-p21-DREAM signaling independent of RB-E2F. Furthermore, RB has non-canonical functions without binding to E2F and DNA. Such a role of RB supporting DREAM formation may be exerted by the RB-SKP2-p27-cyclin A/E-CDK2-p130-DREAM link. In the current synopsis, the mechanism of regulation by p53-p21-RB signaling is assessed and the overlap with p53-p21-DREAM signaling is examined.

视网膜母细胞瘤蛋白 RB 和转录因子 p53 是中枢肿瘤抑制因子。它们经常被发现在各种肿瘤类型中失活。这两种蛋白质在调节细胞分裂周期中起着核心作用。RB 与转录因子 E2F 家族形成复合物并下调许多基因。在RB-E2F靶基因中，大量编码关键的细胞周期调控基因。RB-E2F 复合物对它们的转录抑制通过 RB 的磷酸化释放，导致细胞周期调节因子的表达。细胞周期蛋白依赖性激酶抑制剂 p21/CDKN1A 可以阻止抑制释放。CDKN1A _基因被 p53 转录激活。这些元素合在一起构成了 p53-p21-RB 信号通路。在 p53 激活后，例如通过病毒感染或诱导 DNA 损伤，p21 表达上调。高水平的 p21 然后导致 RB-E2F 复合物形成和大量细胞周期基因的下调。因此，p53 依赖性转录抑制是间接的。许多调节因子的表达减少导致细胞周期停滞。对相关 p53-p21-DREAM 信号通路控制的 p53-p21-RB 靶标和基因的检查表明，这两组有很大的重叠。从机制上讲，这可以通过在目标启动子的 E2F 位点用 DREAM 转录抑制复合物替换 RB-E2F 复合物来解释。与RB-E2F相比，DREAM 也可以通过 CHR 转录因子结合位点下调基因。这导致独立于 RB-E2F 的 p53-p21-DREAM 信号控制的独特基因组。此外，RB 具有不与 E2F 和 DNA 结合的非规范功能。RB 支持 DREAM 形成的这种作用可能由 RB-SKP2-p27-cyclin A/E-CDK2-p130-DREAM 链接发挥作用。在当前概要中，评估了 p53-p21-RB 信号的调节机制，并检查了与 p53-p21-DREAM 信号的重叠。