Sasai Kaori, Treekitkarnmongkol Warapen, Kai Kazuharu, Katayama Hiroshi, Sen Subrata
Department of Molecular Oncology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan.
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center , Houston, TX , USA.
Front Oncol. 2016 Nov 25;6:247. doi: 10.3389/fonc.2016.00247. eCollection 2016.
Aurora kinases play critical roles in regulating spindle assembly, chromosome segregation, and cytokinesis to ensure faithful segregation of chromosomes during mitotic cell division cycle. Molecular and cell biological studies have revealed that Aurora kinases, at physiological levels, orchestrate complex sequential cellular processes at distinct subcellular locations through functional interactions with its various substrates. Aberrant expression of Aurora kinases, on the other hand, cause defects in mitotic spindle assembly, checkpoint response activation, and chromosome segregation leading to chromosomal instability. Elevated expression of Aurora kinases correlating with chromosomal instability is frequently detected in human cancers. Recent genomic profiling of about 3000 human cancer tissue specimens to identify various oncogenic signatures in The Cancer Genome Atlas project has reported that recurrent amplification and overexpression of Aurora kinase-A characterize distinct subsets of human tumors across multiple cancer types. Besides the well-characterized canonical pathway interactions of Aurora kinases in regulating assembly of the mitotic apparatus and chromosome segregation, growing evidence also supports the notion that deregulated expression of Aurora kinases in non-canonical pathways drive transformation and genomic instability by antagonizing tumor suppressor and exacerbating oncogenic signaling through direct interactions with critical proteins. Aberrant expression of the Aurora kinases-p53 protein family signaling axes appears to be critical in the abrogation of p53 protein family mediated tumor suppressor pathways frequently deregulated during oncogenic transformation process. Recent findings reveal the existence of feedback regulatory loops in mRNA expression and protein stability of these protein families and their consequences on downstream effectors involved in diverse physiological functions, such as mitotic progression, checkpoint response pathways, as well as self-renewal and pluripotency in embryonic stem cells. While these investigations have focused on the functional consequences of Aurora kinase protein family interactions with wild-type p53 family proteins, those involving Aurora kinases and mutant p53 remain to be elucidated. This article presents a comprehensive review of studies on Aurora kinases-p53 protein family interactions along with a prospective view on the possible functional consequences of Aurora kinase-mutant p53 signaling pathways in tumor cells. Additionally, we also discuss therapeutic implications of these findings in Aurora kinases overexpressing subsets of human tumors.
极光激酶在调节纺锤体组装、染色体分离和胞质分裂中发挥关键作用，以确保有丝分裂细胞分裂周期中染色体的准确分离。分子和细胞生物学研究表明，在生理水平上，极光激酶通过与其各种底物的功能相互作用，在不同的亚细胞位置协调复杂的细胞过程顺序。另一方面，极光激酶的异常表达会导致有丝分裂纺锤体组装缺陷、检查点反应激活和染色体分离异常，从而导致染色体不稳定。在人类癌症中经常检测到极光激酶的表达升高与染色体不稳定相关。最近在癌症基因组图谱项目中对约3000个人类癌症组织标本进行的基因组分析，以识别各种致癌特征，报告称极光激酶A的反复扩增和过表达是多种癌症类型中不同人类肿瘤亚群的特征。除了极光激酶在调节有丝分裂装置组装和染色体分离方面已得到充分表征的经典途径相互作用外，越来越多的证据也支持这样一种观点，即极光激酶在非经典途径中的失调表达通过与关键蛋白的直接相互作用拮抗肿瘤抑制因子并加剧致癌信号传导，从而驱动细胞转化和基因组不稳定。极光激酶-p53蛋白家族信号轴的异常表达似乎在致癌转化过程中经常失调的p53蛋白家族介导的肿瘤抑制途径的废除中起关键作用。最近的研究结果揭示了这些蛋白家族在mRNA表达和蛋白质稳定性方面存在反馈调节环，以及它们对参与多种生理功能的下游效应器的影响，如有丝分裂进程、检查点反应途径，以及胚胎干细胞的自我更新和多能性。虽然这些研究集中在极光激酶蛋白家族与野生型p53家族蛋白相互作用的功能后果上，但涉及极光激酶和突变型p53的研究仍有待阐明。本文全面综述了极光激酶-p53蛋白家族相互作用的研究，并对极光激酶-突变型p53信号通路在肿瘤细胞中可能的功能后果进行了前瞻性展望。此外，我们还讨论了这些发现对人类肿瘤中极光激酶过表达亚群的治疗意义。
