近日,凯斯西储大学医学院研究人员发现,当癌细胞中表达的基因Chk1发生突变后,在没有任何化疗药物干预下会导致癌细胞增殖永久性的停止,并引起细胞死亡。这项研究说明了一个前所未有的发现即人为地单独激活Chk1是足以杀死癌细胞的。
有了这一发现,科学家可以阻止癌细胞的扩散。Zhang博士的研究小组在研究基因组完整性的基本机制的同时,意外地发现了人Chk1的突变形式。这种突变的Chk1蛋白的构象改变导致该蛋白以无效形式进入一个活跃的形式。
值得注意的是,该研究小组发现在癌细胞中表达该基因时,Chk1的这种积极的突变形式会永久性停止癌细胞增殖并引起细胞死亡。这提示化疗药物组合Chk1抑制剂可以达到协同杀伤肿瘤作用。细胞应对DNA损伤激活的信号通路,被称为细胞周期检控点。这些基因途径的中心就是蛋白激酶Chk1。
Chk1促进细胞存活包括癌细胞,在压力条件下如化疗药物诱导下,通过短暂阻断细胞周期进程协调修复DNA错误。长期以来,人们一直认为,Chk1抑制与化疗或放疗相结合能大大提高这些疗法的抗癌作用。这种想法已经为多个制药公司所接受,并积极寻找潜在Chk1的抑制剂。到今天为止,没有一种Chk1抑制剂已通过临床试验的第三阶段。这导致Zhang博士团队寻找靶向Chk1的替代策略治疗癌症。
Zhang博士和他的团队未来的研究将考虑两种可能的有办法人为地激活肿瘤细胞Chk1。一种可能性是采用基因治疗的概念使得Chk1的活性突变形式进入癌细胞。另一种是寻找小分子可诱导Chk1发生构象的变化,使它们可以达到癌细胞以激活Chk1分子。最后结果就是永久的抑制细胞增殖和癌症。(生物谷:Bioon.com)
编译自:Researchers discover gene that permanently stops cancer cell proliferation
doi:10.1158/0008-5472.CAN-12-0523
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Autoregulatory Mechanisms of Phosphorylation of Checkpoint Kinase 1
Jingna Wang, Xiangzi Han, and Youwei Zhang
Checkpoint kinase 1 (Chk1), a serine/threonine protein kinase, is centrally involved in cell-cycle checkpoints and cellular response to DNA damage. Phosphorylation of Chk1 at 2 Ser/Gln (SQ) sites, Ser-317 and Ser-345, by the upstream kinase ATR is critical for checkpoint activation. However, the precise molecular mechanisms controlling Chk1 phosphorylation and subsequent checkpoint activation are not well understood. Here, we report unique autoregulatory mechanisms that control protein phosphorylation of human Chk1, as well as checkpoint activation and cell viability. Phosphorylation of Ser-317 is required, but not sufficient, for maximal phosphorylation at Ser-345. The N-terminal kinase domain of Chk1 prevents Chk1 phosphorylation at the C-terminus by ATR in the absence of DNA damage. Loss of the inhibitory effect imposed by the N-terminus causes constitutive phosphorylation of Chk1 by ATR under normal growth conditions, which in turn triggers artificial checkpoints that suppress the S-phase progression. Furthermore, two point mutations were identified that rendered Chk1 constitutively active, and expression of the constitutively active mutant form of Chk1 inhibited cancer cell proliferation. Our findings therefore reveal unique regulatory mechanisms of Chk1 phosphorylation and suggest that expression of constitutively active Chk1 may represent a novel strategy to suppress tumor growth.