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      Central spindle proteins and mitotic kinesins are direct transcriptional targets of MuvB, B-MYB and FOXM1 in breast cancer cell lines and are potential targets for therapy

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          Abstract

          The MuvB multiprotein complex, together with B-MYB and FOXM1 (MMB-FOXM1), plays an essential role in cell cycle progression by regulating the transcription of genes required for mitosis and cytokinesis. In many tumors, B-MYB and FOXM1 are overexpressed as part of the proliferation signature. However, the transcriptional targets that are important for oncogenesis have not been identified. Given that mitotic kinesins are highly expressed in cancer cells and that selected kinesins have been reported as target genes of MMB-FOXM1, we sought to determine which mitotic kinesins are directly regulated by MMB-FOXM1. We demonstrate that six mitotic kinesins and two microtubule-associated non-motor proteins (MAPs) CEP55 and PRC1 are direct transcriptional targets of MuvB, B-MYB and FOXM1 in breast cancer cells. Suppression of KIF23 and PRC1 strongly suppressed proliferation of MDA-MB-231 cells. The set of MMB-FOXM1 regulated kinesins genes and 4 additional kinesins which we referred to as the mitotic kinesin signature (MKS) is linked to poor outcome in breast cancer patients. Thus, mitotic kinesins could be used as prognostic biomarker and could be potential therapeutic targets for the treatment of breast cancer.

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          Most cited references 34

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          Kinesin superfamily motor proteins and intracellular transport.

          Intracellular transport is fundamental for cellular function, survival and morphogenesis. Kinesin superfamily proteins (also known as KIFs) are important molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs. The mechanisms by which different kinesins recognize and bind to specific cargos, as well as how kinesins unload cargo and determine the direction of transport, have now been identified. Furthermore, recent molecular genetic experiments have uncovered important and unexpected roles for kinesins in the regulation of such physiological processes as higher brain function, tumour suppression and developmental patterning. These findings open exciting new areas of kinesin research.
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            Cytokinesis in animal cells.

            Cytokinesis, the final step in cell division, partitions the contents of a single cell into two. In animal cells, cytokinesis occurs through cortical remodeling orchestrated by the anaphase spindle. Cytokinesis relies on a tight interplay between signaling and cellular mechanics and has attracted the attention of both biologists and physicists for more than a century. In this review, we provide an overview of four topics in animal cell cytokinesis: (a) signaling between the anaphase spindle and cortex, (b) the mechanics of cortical remodeling, (c) abscission, and (d) regulation of cytokinesis by the cell cycle machinery. We report on recent progress in these areas and highlight some of the outstanding questions that these findings bring into focus.
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              Kinesins and cancer.

              Kinesins are a family of molecular motors that travel unidirectionally along microtubule tracks to fulfil their many roles in intracellular transport or cell division. Over the past few years kinesins that are involved in mitosis have emerged as potential targets for cancer drug development. Several compounds that inhibit two mitotic kinesins (EG5 (also known as KIF11) and centromere-associated protein E (CENPE)) have entered Phase I and II clinical trials either as monotherapies or in combination with other drugs. Additional mitotic kinesins are currently being validated as drug targets, raising the possibility that the range of kinesin-based drug targets may expand in the future.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                14 February 2017
                3 January 2017
                : 8
                : 7
                : 11160-11172
                Affiliations
                1 Theodor Boveri Institute, Biocenter, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, University of Wuerzburg, University of Wuerzburg, Wuerzburg, Germany
                Author notes
                Correspondence to: Stefan Gaubatz, stefan.gaubatz@ 123456biozentrum.uni-wuerzburg.de
                Article
                14466
                10.18632/oncotarget.14466
                5355254
                28061449
                Copyright: © 2017 Wolter et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Categories
                Research Paper

                Oncology & Radiotherapy

                b-myb, foxm1, muvb, dream, kinesin

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