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      The Aurora Kinases in Cell Cycle and Leukemia

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      Oncogene

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          Abstract

          The Aurora kinases, which include Aurora A (AURKA), Aurora B (AURKB) and Aurora C (AURKC), are serine/threonine kinases required for the control of mitosis (AURKA and AURKB) and meiosis (AURKC). Since their discovery nearly twenty years ago, Aurora kinases have been studied extensively in cell and cancer biology 1 . Several early studies found that Aurora kinases are amplified and overexpressed at the transcript and protein level in various malignancies, including several types of leukemia. These discoveries and others provided a rationale for the development of small molecule inhibitors of Aurora kinases as leukemia therapies. The first generation of Aurora kinase inhibitors did not fare well in clinical trials, owing to poor efficacy and high toxicity. However, the creation of second generation, highly selective Aurora kinase inhibitors has increased the enthusiasm for targeting these proteins in leukemia. This review will describe the functions of each Aurora kinase, summarize their involvement in leukemia and discuss inhibitor development and efficacy in leukemia clinical trials.

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          Most cited references141

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          Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells.

          The bcr-abl oncogene, present in 95% of patients with chronic myelogenous leukemia (CML), has been implicated as the cause of this disease. A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr-Abl fusion protein. Cellular proliferation and tumor formation by Bcr-Abl-expressing cells were specifically inhibited by this compound. In colony-forming assays of peripheral blood or bone marrow from patients with CML, there was a 92-98% decrease in the number of bcr-abl colonies formed but no inhibition of normal colony formation. This compound may be useful in the treatment of bcr-abl-positive leukemias.
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            Cancer. Addiction to oncogenes--the Achilles heal of cancer.

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              Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery.

              Polo-like kinase-1 (PLK1) is an essential mitotic kinase regulating multiple aspects of the cell division process. Activation of PLK1 requires phosphorylation of a conserved threonine residue (Thr 210) in the T-loop of the PLK1 kinase domain, but the kinase responsible for this has not yet been affirmatively identified. Here we show that in human cells PLK1 activation occurs several hours before entry into mitosis, and requires aurora A (AURKA, also known as STK6)-dependent phosphorylation of Thr 210. We find that aurora A can directly phosphorylate PLK1 on Thr 210, and that activity of aurora A towards PLK1 is greatly enhanced by Bora (also known as C13orf34 and FLJ22624), a known cofactor for aurora A (ref. 7). We show that Bora/aurora-A-dependent phosphorylation is a prerequisite for PLK1 to promote mitotic entry after a checkpoint-dependent arrest. Importantly, expression of a PLK1-T210D phospho-mimicking mutant partially overcomes the requirement for aurora A in checkpoint recovery. Taken together, these data demonstrate that the initial activation of PLK1 is a primary function of aurora A.
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                Author and article information

                Journal
                8711562
                6325
                Oncogene
                Oncogene
                Oncogene
                0950-9232
                1476-5594
                4 March 2014
                17 March 2014
                29 January 2015
                29 July 2015
                : 34
                : 5
                : 537-545
                Affiliations
                Northwestern University, Chicago IL 60611
                Author notes
                [* ]Corresponding Author: John D. Crispino, Northwestern University, Division of Hematology/Oncology, 303 East Superior Street, Lurie 5-113, Chicago, IL 60611, j-crispino@ 123456northwestern.edu , 312-503-1504
                Article
                NIHMS558868
                10.1038/onc.2014.14
                4167158
                24632603
                ce186431-a6f5-4950-b407-53c7b62e5a5a

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                Oncology & Radiotherapy
                Oncology & Radiotherapy

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