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Chk1防止DNA损伤的S期肿瘤细胞进行异常的有丝分裂
  • ISSN号：0023-074X
  • 期刊名称：《科学通报》
  • 时间：0
  • 分类：Q523[生物学—生物化学] Q78[生物学—分子生物学]
  • 作者机构：[1]中国科学技术大学合肥微尺度物质科学国家实验室(研究部)中国科学技术大学生命科学学院系统生物学系,安徽合肥230027, [2]Morehouse School of Medicine,Department of Physiology,Atlanta,GA 30310,USA, [3]中国科学院系统生物学重点实验室中国科学院上海生命科学研究院生物化学与细胞生物学研究所,上海200031
  • 相关基金：国家自然科学基金创新研究群体项目（批准号：30821065）和国家重点基础研究发展计划资助项目（批准号：2006CB503900）.
作者： 李小方, Tarsha Ward, 姚雪彪, 吴家睿
关键词： 细胞周期, DNA损伤检查点, DNA复制检查点, CHK1, 甲磺酸甲酯
中文摘要：

为探讨在p53失活的肿瘤细胞中DNA甲基化试剂引发的DNA损伤对于细胞周期的影响，我们将同步化在G1，S和G2／M期的HeLa细胞分别进行甲磺酸甲酯（MMS）处理。MMS的处理结果表明，各个时相的细胞周期进程均发生延迟或阻滞，其中S期细胞对药物最为敏感。进一步的分子机理研究表明，3个时相中ATM-Chk2和p38 MAPK通路均被激活，但是Chk1仅在s期中被活化，提示Chk1特异地参与了S期的DNA损伤检查点（DNA damage checkpoint）或者DNA复制检查点（DNA replication checkpoint）的作用。为了进一步确定Chk1在S期的检查点功能，用专一的小分子抑制剂抑制Chk1的磷酸化，发现被MMS处理的S期细胞能在未完成复制的情况下进行异常的有丝分裂，提示Chk1主要是在HeLa细胞s期的DNA损伤检查点而不是DNA复制检查点发挥其作用。另外，本研究还检查了参与G2／M期进程的cyclin B1的表达变化情况。在MMS处理的S期细胞中，cyclin B1表达量不能上调；而在加入Chk1抑制剂处理后，cycfin B1则有所增加。这一结果进一步支持DNA损伤S期细胞在Chk1失活时进入异常有丝分裂的推论。研究结果表明，Chk1是MMS诱发的HeLa细胞S期DNA损伤检查点的专一性的重要蛋白激酶；当MMS引发DNA损伤后，上游蛋白激酶对Chk1进行磷酸化，从而激活了s期的DNA损伤检查点，阻止细胞进入G2／M期。由于这一过程不依赖于p53的活性，因此Chk1有可能作为p53失活的肿瘤细胞的药物靶标。

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期刊信息
  • 《科学通报》
  • 北大核心期刊（2011版）
  • 主管单位:中国科学院
  • 主办单位:中国科学院
  • 主编：周光召
  • 地址：北京东黄城根北街16号
  • 邮编：100717
  • 邮箱：csb@scichina.org
  • 电话：010-64036120 64012686
  • 国际标准刊号：ISSN：0023-074X
  • 国内统一刊号：ISSN：11-1784/N
  • 邮发代号:80-213
  • 获奖情况:
  • 首届国家期刊奖,中国期刊方阵“双高”期刊,第三届中国出版政府奖
  • 国内外数据库收录:
  • 美国化学文摘（网络版）,美国数学评论（网络版）,美国工程索引,日本日本科学技术振兴机构数据库,中国中国科技核心期刊,中国北大核心期刊（2004版）,中国北大核心期刊（2008版）,中国北大核心期刊（2011版）,中国北大核心期刊（2014版）,中国北大核心期刊（2000版）
  • 被引量:81792