RB activation defect in tumor cell lines
RB activation defect in tumor cell lines
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DOI：
10.1073/pnas.212519499
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发表时间：
2002-10-29
影响因子：
11.1
通讯作者：
Mittnacht, S
中科院分区：
文献类型：
--
作者：
Broceño, C;Wilkie, S;Mittnacht, S
视网膜母细胞瘤 (RB) 蛋白在细胞退出 M 期并响应环境应激（包括 DNA 损伤）时通过去磷酸化而被激活。我们在这里首次提供证据表明这些反应在肿瘤衍生细胞系的子集中受到协调影响。我们发现这些细胞在进展为 G(1) 的过程中 RB 去磷酸化并不明显。重要的是，这些细胞在 S 期 DNA 损伤后也不会对 RB 激活做出反应。此外，因此，它们表现出与 RB 细胞典型相关的表型，在 DNA 损伤后显示加速凋亡，在纺锤体检查点激活后显示 DNA 重新复制。大量文献提供的证据表明，控制 RB 失活的控制在肿瘤中丢失。这里给出的结果表明逆反应，即从非活性前体激活 RB，也可能受到损害。我们的研究结果表明，这种类型的缺陷可能与对 DNA 损伤的超敏反应以及纺锤体检查点激活导致的基因组不稳定性增加有关，因此具有潜在的重要医学意义。
Activation of the retinoblastoma (RB) protein through dephosphorylation arises in cells upon exit from M phase and in response to environmental stresses, including DNA damage. We provide here for the first time evidence that these responses are coordinately affected in a subset of tumor derived cell lines. We find that RB dephosphorylation is not apparent in these cells during progression into G(1). Importantly these cells also do not respond with RB activation after DNA damage during S phase. Moreover and as a consequence they display phenotypes classically associated with RB- cells, showing accelerated apoptosis after DNA damage and DNA re-replication after spindle-checkpoint activation. A large body of literature provides evidence that controls governing inactivation of RB are lost in tumors. The results presented here indicate that the reverse reaction, namely the activation of RB from an inactive precursor, may also be compromised. Our findings indicate that this type of defect may be coupled with hypersensitivity to DNA damage and an increase in genomic instability in response to spindle-checkpoint activation thus bearing potentially important medical implications.