Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control

Eva Hernando, Zaher Nahlé, Gloria Juan, Elena Diaz-Rodriguez, Miguel Alaminos, Michael Hemann, Loren Michel, Vivek Mittal, William Gerald, Robert Benezra, Scott W. Lowe () and Carlos Cordon-Cardo
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Eva Hernando: Memorial Sloan-Kettering Cancer Center
Zaher Nahlé: Cold Spring Harbor Laboratory
Gloria Juan: Memorial Sloan-Kettering Cancer Center
Elena Diaz-Rodriguez: Memorial Sloan-Kettering Cancer Center
Miguel Alaminos: Memorial Sloan-Kettering Cancer Center
Michael Hemann: Cold Spring Harbor Laboratory
Loren Michel: Memorial Sloan-Kettering Cancer Center
Vivek Mittal: Cold Spring Harbor Laboratory
William Gerald: Memorial Sloan-Kettering Cancer Center
Robert Benezra: Memorial Sloan-Kettering Cancer Center
Scott W. Lowe: Cold Spring Harbor Laboratory
Carlos Cordon-Cardo: Memorial Sloan-Kettering Cancer Center

Nature, 2004, vol. 430, issue 7001, 797-802

Abstract: Abstract Advanced human cancers are invariably aneuploid, in that they harbour cells with abnormal chromosome numbers1,2. 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 cancers1. These mutations promote tumour development by deregulating the E2F family of transcription factors leading to uncontrolled cell cycle progression3. 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.

Date: 2004
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DOI: 10.1038/nature02820

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