Department of Molecular Oncology, University Medical Center Göttingen, Göttingen, Germany.
Clin Cancer Res. 2011 Feb 1;17(3):401-5. doi: 10.1158/1078-0432.CCR-10-1215. Epub 2010 Nov 18.
CHK2 is a multiorgan tumor susceptibility gene that encodes for a serine/threonine protein kinase involved in the response to cellular DNA damage. After ATM-mediated phosphorylation, the activated Chk2 kinase can act as a signal transducer and phosphorylate a variety of substrates, including the Cdc25 phosphatases, p53, PML, E2F-1, and Brca1, which has been associated with halting the cell cycle, the initiation of DNA repair, and the induction of apoptosis after DNA damage. In addition, recent work has revealed another, DNA-damage-independent function of Chk2 during mitosis that is required for proper mitotic spindle assembly and maintenance of chromosomal stability. This novel role involves a mitotic phosphorylation of the tumor suppressor Brca1 by the Chk2 kinase. On the basis of its role during DNA damage response, Chk2 has been suggested as an anticancer therapy target, but given its recently discovered new function and its role as a tumor suppressor, it is questionable whether inhibition of Chk2 is indeed beneficial for anticancer treatment. However, investigators may be able to exploit the loss of CHK2 in human tumors to develop novel therapies based on synthetic lethal interactions.
CHK2 是一种多器官肿瘤易感性基因，编码一种丝氨酸/苏氨酸蛋白激酶，参与细胞 DNA 损伤的反应。在 ATM 介导的磷酸化作用后，激活的 Chk2 激酶可以作为信号转导分子，磷酸化多种底物，包括 Cdc25 磷酸酶、p53、PML、E2F-1 和 Brca1，这些底物与细胞周期停滞、DNA 修复的启动以及 DNA 损伤后的细胞凋亡诱导有关。此外，最近的研究揭示了 Chk2 在有丝分裂过程中的另一个与 DNA 损伤无关的功能，该功能对于有丝分裂纺锤体的正确组装和染色体稳定性的维持是必需的。这个新的作用涉及 Chk2 激酶对肿瘤抑制因子 Brca1 的有丝分裂磷酸化。基于其在 DNA 损伤反应中的作用，Chk2 被认为是一种抗癌治疗靶点，但鉴于其最近发现的新功能及其作为肿瘤抑制因子的作用，抑制 Chk2 是否确实有利于抗癌治疗是值得怀疑的。然而，研究人员可能能够利用人类肿瘤中 CHK2 的缺失来开发基于合成致死相互作用的新型疗法。
