title: 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.
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.
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, University of Wuerzburg, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Wolter
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, University of Wuerzburg, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Hanselmann
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, University of Wuerzburg, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Grit
authors.initials: G
authors.lastname: Pattschull
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, University of Wuerzburg, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Schruf
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Wuerzburg and Comprehensive Cancer Center Mainfranken, University of Wuerzburg, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gaubatz
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D000072278:Forkhead Box Protein M1 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D016547:Kinesins / Q000235:genetics* / Q000378:metabolism; D061986:MCF-7 Cells; D008938:Mitosis / Q000235:genetics; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D008941:Spindle Apparatus / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; C064352:MYBL2 protein, human; D046912:Multiprotein Complexes; D020033:Protein Isoforms; D021122:Protein Subunits; D015534:Trans-Activators; D016547:Kinesins
keywords: B-MYB; DREAM; FOXM1; MuvB; kinesin