Macarulla Teresa, Ramos Francisco Javier, Tabernero Josep
Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain.
Recent Pat Anticancer Drug Discov. 2008 Jun;3(2):114-22. doi: 10.2174/157489208784638785.
Aurora kinases (AK) are the name given to a family of Serine/threonine (Ser/Thr) protein kinases. These proteins represent a novel family of kinases crucial for cell cycle control. The cell division process is one of the hallmarks of every living organism. Within the complete cell-cycle process, mitosis constitutes one of the most critical steps. The main purpose of mitosis is to segregate sister chromatics into two daughters cells. It is a complex biologic process, and errors in this mechanism can lead to genomic instability, a condition associated with tumorigenesis. This process is tightly regulated by several proteins, some of them acting as check-points that ultimately ensure the correct temporal and spatial coordination of this critical biologic process. Among this network of mitotic regulators, AK play a critical role in cellular division by controlling chromatid segregation. Three AK family members have been identified in mammalian cells: A, B, and C. These proteins are implicated in several vital events in mitosis. In experimental models, overexpression of AK can induce spindle defects, chromosome mis-segregation, and malignant transformation. Conversely, downregulation of AK expression cause mitotic arrest and apoptosis in tumor cell lines. The expression levels of human AK are increased in certain types of cancer including breast, colon, pancreatic, ovarian, and gastric tumors. This observation has lent an interest to this family of kinases as potential drug targets for development of new anticancer therapies. This review focuses in recent progress in the role of AK in tumorogenesis and the development of new anticancer drug against AK proteins. This manuscript also includes some relevant patents as well.
极光激酶（AK）是给丝氨酸/苏氨酸（Ser/Thr）蛋白激酶家族的命名。这些蛋白代表了对细胞周期控制至关重要的一个新型激酶家族。细胞分裂过程是每个生物体的标志性特征之一。在完整的细胞周期过程中，有丝分裂是最关键的步骤之一。有丝分裂的主要目的是将姐妹染色单体分离到两个子细胞中。这是一个复杂的生物学过程，该机制中的错误会导致基因组不稳定，这是一种与肿瘤发生相关的状况。这个过程受到几种蛋白质的严格调控，其中一些蛋白质起到检查点的作用，最终确保这个关键生物学过程的正确时间和空间协调。在这个有丝分裂调节因子网络中，AK通过控制染色单体分离在细胞分裂中发挥关键作用。在哺乳动物细胞中已鉴定出三个AK家族成员：A、B和C。这些蛋白质参与有丝分裂中的几个重要事件。在实验模型中，AK的过表达可诱导纺锤体缺陷、染色体错误分离和恶性转化。相反，AK表达的下调会导致肿瘤细胞系的有丝分裂停滞和凋亡。在包括乳腺癌、结肠癌、胰腺癌、卵巢癌和胃癌等某些类型的癌症中，人类AK的表达水平会升高。这一观察结果使人们对这个激酶家族作为开发新抗癌疗法的潜在药物靶点产生了兴趣。本综述重点关注AK在肿瘤发生中的作用以及针对AK蛋白的新型抗癌药物的研发进展。本手稿还包括一些相关专利。
