Ha Geun-Hyoung, Breuer Eun-Kyoung Yim
Department of Radiation Oncology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.
Biochem Res Int. 2012;2012:195903. doi: 10.1155/2012/195903. Epub 2012 Jul 19.
Mitosis is tightly regulated and any errors in this process often lead to aneuploidy, genomic instability, and tumorigenesis. Deregulation of mitotic kinases is significantly associated with improper cell division and aneuploidy. Because of their importance during mitosis and the relevance to cancer, mitotic kinase signaling has been extensively studied over the past few decades and, as a result, several mitotic kinase inhibitors have been developed. Despite promising preclinical results, targeting mitotic kinases for cancer therapy faces numerous challenges, including safety and patient selection issues. Therefore, there is an urgent need to better understand the molecular mechanisms underlying mitotic kinase signaling and its interactive network. Increasing evidence suggests that tumor suppressor p53 functions at the center of the mitotic kinase signaling network. In response to mitotic spindle damage, multiple mitotic kinases phosphorylate p53 to either activate or deactivate p53-mediated signaling. p53 can also regulate the expression and function of mitotic kinases, suggesting the existence of a network of mutual regulation, which can be positive or negative, between mitotic kinases and p53 signaling. Therefore, deciphering this regulatory network will provide knowledge to overcome current limitations of targeting mitotic kinases and further improve the results of targeted therapy.
有丝分裂受到严格调控，该过程中的任何错误通常都会导致非整倍体、基因组不稳定和肿瘤发生。有丝分裂激酶的失调与细胞分裂异常和非整倍体显著相关。由于它们在有丝分裂过程中的重要性以及与癌症的相关性，在过去几十年中对有丝分裂激酶信号传导进行了广泛研究，因此开发了几种有丝分裂激酶抑制剂。尽管临床前结果很有前景，但针对有丝分裂激酶进行癌症治疗面临诸多挑战，包括安全性和患者选择问题。因此，迫切需要更好地了解有丝分裂激酶信号传导及其相互作用网络的分子机制。越来越多的证据表明，肿瘤抑制因子p53在有丝分裂激酶信号网络中发挥核心作用。响应有丝分裂纺锤体损伤，多种有丝分裂激酶使p53磷酸化，以激活或失活p53介导的信号传导。p53还可以调节有丝分裂激酶的表达和功能，这表明在有丝分裂激酶和p53信号传导之间存在一个相互调节的网络，这种调节可以是正向的或负向的。因此，破解这个调控网络将为克服目前针对有丝分裂激酶的局限性提供知识，并进一步改善靶向治疗的效果。
