title: Geminin overexpression induces mammary tumors via suppressing cytokinesis.
abstract: Aneuploidy plays an important role in the development of cancer. Here, we uncovered an oncogenic role for geminin in mitotic cells. In addition to chromatin, tyrosine phosphorylated geminin also localizes to centrosome, spindle, cleavage furrow and midbody during mitosis. Geminin binding to Aurora B prevents its binding to INCENP, and thus activation leading to lack of histone H3-(serine 10) phosphorylation, chromosome condensation failure, aborted cytokinesis and the formation of aneuploid, drug resistance cells. Geminin overexpressing human mammary epithelial cells form aneuploid, aggressive tumors in SCID mice. Geminin is overexpressed in more than half of all breast cancers analyzed. The current study reveals that geminin is a genuine oncogene that promotes cytokinesis failure and production of aneuploid, aggressive breast tumors when overexpressed and thus a worthy therapeutic target (oncotarget) for aggressive breast cancer.
authors.affiliation: Cancer Institute and Department of Biochemistry, University of Mississippi Medical Center, 2500 N. State St., G651-6, Jackson, MS 39216, USA.
authors.forename: Zannel
authors.initials: Z
authors.lastname: Blanchard
authors.forename: Rohit
authors.initials: R
authors.lastname: Malik
authors.forename: Nicole
authors.initials: N
authors.lastname: Mullins
authors.forename: Christine
authors.initials: C
authors.lastname: Maric
authors.forename: Hugh
authors.initials: H
authors.lastname: Luk
authors.forename: David
authors.initials: D
authors.lastname: Horio
authors.forename: Brenda
authors.initials: B
authors.lastname: Hernandez
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Killeen
authors.forename: Wael M
authors.initials: WM
authors.lastname: Elshamy
mesh_terms: D000782:Aneuploidy; D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001549:Benzamides / Q000494:pharmacology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D048749:Cytokinesis / Q000502:physiology*; D005260:Female; D064248:Geminin; D006657:Histones / Q000378:metabolism; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics*; D051379:Mice; D016513:Mice, SCID; D008938:Mitosis; D009857:Oncogenes; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism
chemical_list: C474722:4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline; D001549:Benzamides; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; C577995:GMNN protein, human; D064248:Geminin; D006657:Histones; C513185:Incenp protein, mouse; D011799:Quinazolines; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases