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

Hernando, E., Nahle, Z., Juan, G., Diaz-Rodriguez, E., Alaminos, M., Hemann, M., Michel, L., Mittal, V., Gerald, W., Benezra, R., Lowe, S. W., Cordon-Cardo, C. (August 2004) Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature, 430 (7001). pp. 797-802. ISSN 0028-0836

URL: http://www.nature.com/nature/journal/v430/n7001/ab...
DOI: 10.1038/nature02820

Abstract

Advanced human cancers are invariably aneuploid, in that they harbour cells with abnormal chromosome numbers(1,2). 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 cancers(1). These mutations promote tumour development by deregulating the E2F family of transcription factors leading to uncontrolled cell cycle progression(3). 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.

Item Type: Paper
Uncontrolled Keywords: SISTER-CHROMATID SEPARATION sister chromatid separation SPINDLE CHECKPOINT spindle checkpoint CHROMOSOME chromosome instability INSTABILITY MAMMALIAN-CELLS mammalian cells BLADDER-CANCER bladder cancer GENES genes MAD2 E2F DISRUPTION disruption PROTEINS proteins
Subjects: diseases & disorders > cancer
diseases & disorders > cancer > cancer types > retinoblastoma
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
CSHL Authors:
Communities: CSHL labs > Lowe lab
CSHL labs > Mittal lab
Depositing User: CSHL Librarian
Date: August 2004
Date Deposited: 01 Feb 2012 18:41
Last Modified: 01 Feb 2012 18:41
URI: http://repository.cshl.edu/id/eprint/22387

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