近日，凱斯西儲大學醫(yī)學院研究人員發(fā)現(xiàn),，當癌細胞中表達的基因Chk1發(fā)生突變后,，在沒有任何化療藥物干預下會導致癌細胞增殖永久性的停止，并引起細胞死亡,。這項研究說明了一個前所未有的發(fā)現(xiàn)即人為地單獨激活Chk1是足以殺死癌細胞的,。
有了這一發(fā)現(xiàn)，科學家可以阻止癌細胞的擴散,。Zhang博士的研究小組在研究基因組完整性的基本機制的同時,，意外地發(fā)現(xiàn)了人Chk1的突變形式。這種突變的Chk1蛋白的構(gòu)象改變導致該蛋白以無效形式進入一個活躍的形式,。
值得注意的是,，該研究小組發(fā)現(xiàn)在癌細胞中表達該基因時，Chk1的這種積極的突變形式會永久性停止癌細胞增殖并引起細胞死亡,。這提示化療藥物組合Chk1抑制劑可以達到協(xié)同殺傷腫瘤作用,。細胞應對DNA損傷激活的信號通路，被稱為細胞周期檢控點,。這些基因途徑的中心就是蛋白激酶Chk1,。
Chk1促進細胞存活包括癌細胞，在壓力條件下如化療藥物誘導下,，通過短暫阻斷細胞周期進程協(xié)調(diào)修復DNA錯誤,。長期以來，人們一直認為,，Chk1抑制與化療或放療相結(jié)合能大大提高這些療法的抗癌作用,。這種想法已經(jīng)為多個制藥公司所接受，并積極尋找潛在Chk1的抑制劑,。到今天為止,，沒有一種Chk1抑制劑已通過臨床試驗的第三階段,。這導致Zhang博士團隊尋找靶向Chk1的替代策略治療癌癥。
Zhang博士和他的團隊未來的研究將考慮兩種可能的有辦法人為地激活腫瘤細胞Chk1,。一種可能性是采用基因治療的概念使得Chk1的活性突變形式進入癌細胞,。另一種是尋找小分子可誘導Chk1發(fā)生構(gòu)象的變化，使它們可以達到癌細胞以激活Chk1分子,。最后結(jié)果就是永久的抑制細胞增殖和癌癥,。（生物谷：Bioon.com）
編譯自：Researchers discover gene that permanently stops cancer cell proliferation
doi:10.1158/0008-5472.CAN-12-0523
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PMID:
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.
