The Aurora kinases: Role in cell transformation and tumorigenesis.
The Aurora kinases: Role in cell transformation and tumorigenesis.
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DOI：
10.1023/a:1023789416385
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发表时间：
2003-12-01
影响因子：
9.2
通讯作者：
Sen, Subrata
中科院分区：
文献类型：
--
作者：
Katayama, Hiroshi;Brinkley, William R.;Sen, Subrata
极光激酶代表着一个新的丝氨酸/苏氨酸激酶家族，已被确定为有丝分裂细胞分裂过程的关键调节因子。到目前为止，该激酶家族的三个成员分别被称为Aurora-A、Aurora-B和Aurora-C，它们是典型的酵母Ipl1和果蝇极光激酶的同源基因，它们参与了中心体功能的调节、两极纺锤体的组装和染色体分离过程。哺乳动物激酶家族的三个成员都有一个高度保守的催化结构域，具有一个大小不一的短C末端结构域和一个N末端结构域。自从大约五年前他们被发现以来，广泛的研究集中在了解这些激酶的生物学作用和阐明它们调节细胞增殖和维持正常细胞表型的通路。人们对这一主题产生了浓厚的兴趣，因为据报道，所有三个极光激酶家族成员在许多人类癌症中都过表达，并且在某些情况下，高表达与染色体不稳定和临床侵袭性疾病有关。该家族中的一个成员Aurora-A的异位过表达被证明在细胞中诱导了致癌转化。与大多数已知的其他癌基因不同，到目前为止，该激酶家族的成员在细胞周期的G2-M期表达和激活的水平最高。极光激酶定位于间期细胞的中心体、两极纺锤体的两极和有丝分裂器官的中体。Aurora-A和Aurora-B激酶的底物包括激动素样马达蛋白、纺锤体蛋白、组蛋白H3蛋白、动粒蛋白和肿瘤抑制蛋白P53。Aurora激酶被鉴定为RasGAP Src同源3结构域结合蛋白，也可能是RAS通路中与肿瘤发生相关的潜在效应因子。在人类癌细胞中检测到极光激酶的异常高表达有助于解释导致许多与恶性细胞相关的细胞表型发展的潜在生物学机制。这些机制的确定为未来设计新的癌症靶向疗法提供了可能性。
Aurora kinases representing a novel family of serine/threonine kinases have been identified as key regulators of the mitotic cell division process. The three members of this kinase family, identified so far, referred to as Aurora-A, Aurora-B and Aurora-C kinases, are close homologues of the prototypic yeastIpl1andDrosophila aurorakinases, which are known to be involved in the regulation of centrosome function, bipolar spindle assembly and chromosome segregation processes. All three members of the mammalian kinase family have a catalytic domain that is highly conserved with a short C-terminal domain and an N-terminal domain of varying sizes. Following their discovery about five years ago, extensive research has focused on understanding the biological roles of these kinases and elucidation of their pathways, which regulate cell proliferation and maintenance of normal cellular phenotypes. Significant interest in the subject was generated since all three Aurora kinases family members were reported to be overexpressed in many human cancers, and elevated expression has been correlated with chromosomal instability and clinically aggressive disease in some instances. Ectopic overexpression of one member of the family, Aurora-A, was shown to induce oncogenic transformation in cells. Unlike most other putative oncogenes identified, so far, members of this kinase family are expressed and active at the highest level during G2-M phase of the cell cycle. Aurora kinases are localized at the centrosomes of interphase cells, at the poles of the bipolar spindle and in the midbody of the mitotic apparatus. Substrates identified for the Aurora-A and Aurora-B kinases, include a kinesin-like motor protein, spindle apparatus proteins, histone H3 protein, kinetochore protein and the tumor suppressor protein p53. Identification of Aurora kinases as RasGAP Src homology 3 domain binding protein, also implicates these kinases as potential effectors in the Ras pathway relevant to oncogenesis. Abnormal elevated expression of Aurora kinases detected in human cancer cells could help explain the underlying biological mechanisms responsible for the development of many cellular phenotypes associated with malignant cells. Identification of these mechanisms offers the possibility of designing novel targeted therapies for cancer in the future.