Human prostate epithelium lacks Wee1A-mediated DNA damage-induced checkpoint enforcement
Human prostate epithelium lacks Wee1A-mediated DNA damage-induced checkpoint enforcement
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DOI：
10.1073/pnas.0609299104
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发表时间：
2007-04-24
影响因子：
11.1
通讯作者：
Laiho, Marikki
中科院分区：
文献类型：
--
作者：
Hallstrom, Taija M. Kiviharju-af;Jaamaa, Sari;Laiho, Marikki
细胞DNA损伤触发DNA损伤反应途径，并导致细胞周期检查点的实施，这些检查点对于维持基因组完整性至关重要，并在肿瘤发生的早期阶段被激活。前列腺癌的一个特点是发病率高、多灶性。为了解决前列腺中DNA损伤检查点的功能，我们分析了人原代前列腺上皮细胞（HPEC）和新鲜分离的人前列腺组织对γ-照射的反应。我们发现，γ-辐射激活共济失调毛细血管扩张症突变相关的DNA损伤反应途径中的HPEC，但磷酸化组蛋白H2 AX（γ H2 AX）病灶的清除延迟。令人惊讶的是，γ射线照射的HPEC不能强制细胞周期检查点阻滞，并持续细胞周期蛋白依赖性激酶2（Cdk 2）相关的激酶活性，因为缺乏抑制Cdk磷酸化的Wee 1A酪氨酸激酶。我们进一步表明，HPEC表达低水平的Wee 1A，异位Wee 1A有效地挽救了检查点。我们概括了在离体照射的人前列腺组织的上皮中不存在检查点反应，尽管γ H2 AX的强烈诱导。研究结果表明，前列腺上皮细胞具有令人惊讶的控制检查点停滞的能力，缺乏这种能力可能会导致DNA损伤的增加。
Cellular DNA damage triggers the DNA damage response pathway and leads to enforcement of cell cycle checkpoints, which are essential for the maintenance of genomic integrity and are activated in early stages of tumorigenesis. A special feature of prostate cancer is its high incidence and multifocality. To address the functionality of DNA damage checkpoints in the prostate, we analyzed the responses of human primary prostate epithelial cells (HPECs) and freshly isolated human prostate tissues to gamma- irradiation. We find that gamma-irradiation activates the ataxia telangiectasia mutated-associated DNA damage response pathway in the HPECs but that the clearance of phosphorylated histone H2AX (gamma H2AX) foci is delayed. Surprisingly, gamma-irradiated HPECs were unable to enforce cell cycle checkpoint arrest and had sustained cyclin-dependent kinase 2 (Cdk2)-associated kinase activity because of a lack of inhibitory Cdk phosphorylation by Wee1A tyrosine kinase. We further show that HPECs express low levels of Wee1A and that ectopic Wee1A efficiently rescues the checkpoints. We recapitulate the absence of checkpoint responses in epithelium of ex vivo irradiated human prostate tissue despite robust induction of gamma H2AX. The findings show that prostate epithelium has a surprising inability to control checkpoint arrest, the lack of which may predispose to accrual of DNA lesions.