title: Simultaneous reduction of MAD2 and BUBR1 expression induces mitotic spindle alterations associated with p53 dependent cell cycle arrest and death.
abstract: Most human tumors are characterized by aneuploidy that is believed to be the consequence of chromosomal instability (CIN). The mechanism(s) leading to aneuploidy and the pathways that allow its tolerance are not completely understood. The Spindle Assembly Checkpoint (SAC) is a cellular surveillance mechanism working during mitosis, and alterations of genes that encode components of the SAC weakening the mitotic checkpoint, induce aneuploidy by chromosome mis-segregation. We induced aneuploidy in near-diploid tumor cells by simultaneous depletion of the SAC proteins MAD2 and BUBR1 by RNA interference in the attempt to gain further insight on the cellular responses to aneuploidy. Individual reduction of MAD2 and BUBR1 protein levels caused defective mitosis and aneuploidy, while co-depletion of MAD2 and BUBR1 caused cell cycle arrest and cell death in addition to aneuploidy. The simultaneous reduction of the two SAC proteins induced high percentage of hyperdiploid cells and p53 stabilization suggesting that hyperdiploidy could activate a p53 controlled pathway. The results indicate that p53 is required to induce cell cycle arrest and cell death when the mitotic checkpoint is strongly perturbed, thereby preventing aneuploid cell propagation.
authors.affiliation: Department of Biological Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo Viale delle Scienze, Palermo, 90128, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Lentini
authors.forename: Desirèe
authors.initials: D
authors.lastname: Piscitello
authors.forename: Lorena
authors.initials: L
authors.lastname: Veneziano
authors.forename: Aldo
authors.initials: A
authors.lastname: Di Leonardo
mesh_terms: D000782:Aneuploidy; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006801:Humans; D064246:Mad2 Proteins / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D008941:Spindle Apparatus / Q000378:metabolism*
chemical_list: C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; D034741:RNA, Small Interfering; C584277:BUB1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: cell cycle; cell death; chromosomes