title: Mad2 is a critical mediator of the chromosome instability observed upon Rb and p53 pathway inhibition.
abstract: Multiple mechanisms have been proposed to explain how Rb and p53 tumor suppressor loss lead to chromosome instability (CIN). It was recently shown that Rb pathway inhibition causes overexpression of the mitotic checkpoint gene Mad2, but whether Mad2 overexpression is required to generate CIN in this context is unknown. Here, we show that CIN in cultured cells lacking Rb family proteins requires Mad2 upregulation and that this upregulation is also necessary for CIN and tumor progression in vivo. Mad2 is also repressed by p53 and its upregulation is required for CIN in a p53 mutant tumor model. These results demonstrate that Mad2 overexpression is a critical mediator of the CIN observed upon inactivation of two major tumor suppressor pathways.
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, USA.
authors.forename: Juan-Manuel
authors.initials: JM
authors.lastname: Schvartzman
authors.forename: Pascal H G
authors.initials: PH
authors.lastname: Duijf
authors.forename: Rocio
authors.initials: R
authors.lastname: Sotillo
authors.forename: Courtney
authors.initials: C
authors.lastname: Coker
authors.forename: Robert
authors.initials: R
authors.lastname: Benezra
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000502:physiology*; D049109:Cell Proliferation; D043171:Chromosomal Instability; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D064246:Mad2 Proteins; D008325:Mammary Neoplasms, Experimental / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D012097:Repressor Proteins / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C493956:CDKN1A protein, human; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C577697:MAD2L1 protein, human; D064246:Mad2 Proteins; C577698:Mad2l1 protein, mouse; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53