title: Loss of APC induces polyploidy as a result of a combination of defects in mitosis and apoptosis.
abstract: Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene initiate a majority of colorectal cancers. Acquisition of chromosomal instability is an early event in these tumors. We provide evidence that the loss of APC leads to a partial loss of interkinetochore tension at metaphase and alters mitotic progression. Furthermore, we show that inhibition of APC in U2OS cells compromises the mitotic spindle checkpoint. This is accompanied by a decrease in the association of the checkpoint proteins Bub1 and BubR1 with kinetochores. Additionally, APC depletion reduced apoptosis. As expected from this combination of defects, tetraploidy and polyploidy are consequences of APC inhibition in vitro and in vivo. The removal of APC produced the same defects in HCT116 cells that have constitutively active beta-catenin. These data show that the loss of APC immediately induces chromosomal instability as a result of a combination of mitotic and apoptotic defects. We suggest that these defects amplify each other to increase the incidence of tetra- and polyploidy in early stages of tumorigenesis.
authors.affiliation: Division of Cell and Developmental Biology, University of Dundee, Dundee DD1 5EH, Scotland, UK.
authors.forename: Dina
authors.initials: D
authors.lastname: Dikovskaya
authors.forename: David
authors.initials: D
authors.lastname: Schiffmann
authors.forename: Ian P
authors.initials: IP
authors.lastname: Newton
authors.forename: Abigail
authors.initials: A
authors.lastname: Oakley
authors.forename: Karin
authors.initials: K
authors.lastname: Kroboth
authors.forename: Owen
authors.initials: O
authors.lastname: Sansom
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Jamieson
authors.forename: Valerie
authors.initials: V
authors.lastname: Meniel
authors.forename: Alan
authors.initials: A
authors.lastname: Clarke
authors.forename: Inke S
authors.initials: IS
authors.lastname: Näthke
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D045325:HCT116 Cells; D006657:Histones / Q000032:analysis; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000737:chemistry / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008938:Mitosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D011123:Polyploidy; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering / Q000235:genetics; D008941:Spindle Apparatus / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D051176:beta Catenin / Q000032:analysis / Q000378:metabolism
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C584278:Bub1b protein, mouse; C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D018797:Cell Cycle Proteins; D002843:Chromatin; D019926:Cyclin B; D056744:Cyclin B1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D034741:RNA, Small Interfering; D051176:beta Catenin; D011494:Protein Kinases; C584277:BUB1 protein, human; C584281:Bub1 protein, mouse; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D053148:Caspase 3; D019311:Staurosporine; D017239:Paclitaxel; D015739:Nocodazole