The retinoblastoma tumour suppressor protein (RB) regulates a number of diverse cellular functions including differentiation, angiogenesis, chromatin remodelling, senescence and apoptosis. The best‐characterised function of RB is cell cycle regulation, and it has been considered a phosphoprotein regulated by cyclin‐dependent kinases. In its hypophosphorylated form, RB binds the transcription factor E2F1, arresting the cell cycle in the G1 phase. Here, we show that MDM2 controls the cell cycle through synthesis and degradation of RB protein in a cell cycle condition‐dependent fashion. MDM2 induces G1 cell cycle arrest by enhancing the translation of the RB mRNA under genotoxic stress. Translation requires direct interaction between the RB mRNA and the MDM2 protein that accompanies the RB mRNA to the polysomes. However, MDM2 ubiquitinates and degrades RB protein at the G2/M phase under genotoxic stress. The ATM phosphomimetic mutant MDM2(S395D) corroborates that the effect on the RB levels is dependent on the DNA damage. These results provide the basis of a dual regulatory mechanism by which MDM2 controls cell cycle progression during DNA damage.

中文翻译：

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MDM2 在基因毒性应激期间调节 RB 水平


视网膜母细胞瘤肿瘤抑制蛋白 (RB) 调节许多不同的细胞功能，包括分化、血管生成、染色质重塑、衰老和细胞凋亡。 RB 最典型的功能是细胞周期调节，它被认为是一种受细胞周期蛋白依赖性激酶调节的磷蛋白。在其低磷酸化形式下，RB 结合转录因子 E2F1，将细胞周期停滞在 G1 期。在这里，我们证明 MDM2 通过以细胞周期条件依赖性方式合成和降解 RB 蛋白来控制细胞周期。 MDM2 通过在基因毒性应激下增强RB mRNA 的翻译来诱导 G1 细胞周期停滞。翻译需要RB mRNA 和伴随RB mRNA 到达多聚核糖体的 MDM2 蛋白之间的直接相互作用。然而，在基因毒性应激下，MDM2 在 G2/M 期泛素化并降解 RB 蛋白。 ATM 拟磷突变体 MDM2(S395D) 证实对 RB 水平的影响取决于 DNA 损伤。这些结果为 MDM2 在 DNA 损伤期间控制细胞周期进程的双重调节机制提供了基础。