RB-dependent S-phase response to DNA damage
RB-dependent S-phase response to DNA damage
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DOI：
10.1128/mcb.20.20.7751-7763.2000
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发表时间：
2000-10-01
影响因子：
5.3
通讯作者：
Knudsen, ES
中科院分区：
文献类型：
--
作者：
Knudsen, KE;Booth, D;Knudsen, ES
视网膜母细胞瘤肿瘤抑制蛋白（RB）是一种有效的细胞增殖抑制剂。RB在整个细胞周期中表达，但其抗增殖活性在G（1）/S转换期间被磷酸化中和。RB在由多种生长抑制信号诱导的G（1）阻滞中起重要作用。在这份报告中，RB被证明也需要一个内S期响应DNA损伤。顺铂，足叶乙甙，或丝裂霉素C治疗抑制Rb+/+，但不Rb-/-小鼠胚胎成纤维细胞的S期进展。RB在S期细胞中的去磷酸化在时间上先于DNA合成的抑制。在p21（Cip 1）缺陷细胞中观察到RB的S期去磷酸化和随后的DNA复制抑制。RB依赖的S期内阻滞的诱导持续数天，并与DNA损伤诱导的细胞死亡的保护相关。这些结果表明RB通过抑制细胞周期在G（1）和S期的进展，在响应遗传毒性应激中发挥保护作用。
The retinoblastoma tumor suppressor protein (RB) is a potent inhibitor of cell proliferation. RB is expressed throughout the cell cycle, but its antiproliferative activity is neutralized by phosphorylation during the G(1)/S transition. RB plays an essential role in the G(1) arrest induced by a variety of growth inhibitory signals. In this report, RB is shown to also be required for an intra-S-phase response to DNA damage. Treatment with cisplatin, etoposide, or mitomycin C inhibited S-phase progression in Rb+/+ but not in Rb-/- mouse embryo fibroblasts. Dephosphorylation of RB in S-phase cells temporally preceded the inhibition of DNA synthesis. This S-phase dephosphorylation of RB and subsequent inhibition of DNA replication was observed in p21(Cip1)-deficient cells. The induction of the RB-dependent intra-S-phase arrest persisted for days and correlated with a protection against DNA damage-induced cell death. These results demonstrate that RB plays a protective role in response to genotoxic stress by inhibiting cell cycle progression in G(1) and in S phase.