Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control.
Advanced human cancers are invariably aneuploid, in that they harbour cells with abnormal chromosome numbers. However, the molecular defects underlying this trait, and whether they are a cause or a consequence of the malignant phenotype, are not clear. Mutations that disable the retinoblastoma (Rb) pathway are also common in human cancers. These mutations promote tumour development by deregulating the E2F family of transcription factors leading to uncontrolled cell cycle progression. We show that the mitotic checkpoint protein Mad2 is a direct E2F target and, as a consequence, is aberrantly expressed in cells with Rb pathway defects. Concordantly, Mad2 is overexpressed in several tumour types, where it correlates with high E2F activity and poor patient prognosis. Generation of Rb pathway lesions in normal and transformed cells produces aberrant Mad2 expression and mitotic defects leading to aneuploidy, such that elevated Mad2 contributes directly to these defects. These results demonstrate how chromosome instability can arise as a by-product of defects in cell cycle control that compromise the accuracy of mitosis, and suggest a new model to explain the frequent appearance of aneuploidy in human cancer.
Department of Pathology, Memorial Sloan-Kettering Cancer Center New York, New York 10021, USA.
Eva
E
Hernando
Zaher
Z
Nahlé
Gloria
G
Juan
Elena
E
Diaz-Rodriguez
Miguel
M
Alaminos
Michael
M
Hemann
Loren
L
Michel
Vivek
V
Mittal
William
W
Gerald
Robert
R
Benezra
Scott W
SW
Lowe
Carlos
C
Cordon-Cardo
D000782:Aneuploidy; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D002877:Chromosomes, Human; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050684:E2F Transcription Factors; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D064246:Mad2 Proteins; D051379:Mice; D008938:Mitosis / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D013379:Substrate Specificity; D014157:Transcription Factors / Q000378:metabolism*
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D064246:Mad2 Proteins; C577698:Mad2l1 protein, mouse; C577699:Mad2l2 protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D014157:Transcription Factors