Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control Journal Article
| Authors: | Hernando, E.; NahlĂ©, Z.; Juan, G.; Diaz-RodrĂguez, E.; Alaminos, M.; Hemann, M.; Michel, L.; Mittal, V.; Gerald, W.; Benezra, R.; Lowe, S. W.; Cordon-Cardo, C. |
| Article Title: | Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control |
| Abstract: | 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. |
| Keywords: | immunohistochemistry; signal transduction; controlled study; protein expression; carrier protein; dna binding protein; gene mutation; human cell; genetics; mutation; dna-binding proteins; advanced cancer; pathophysiology; cancer patient; mitosis; accuracy; cell cycle protein; chromosome; mouse; phenotype; animal; metabolism; animals; cell cycle proteins; mice; in situ hybridization, fluorescence; cell cycle; genes; biology; nuclear protein; cell line; transcription factor; cell line, tumor; physiology; carcinogenesis; transcription factors; nuclear proteins; gene expression regulation; cancer genetics; gene expression regulation, neoplastic; fluorescence in situ hybridization; cell culture; messenger rna; tumors; rna, messenger; cell transformation; genomic instability; transcription factor e2f; carrier proteins; substrate specificity; tumor cell line; genome; enzyme specificity; retinoblastoma protein; chromosomes, human; karyotyping; aneuploidy; human chromosome; protein mad2; e2f transcription factors; natural sciences; humans; human; priority journal; article; retinoblastoma (rb); mad2l1 protein, mouse; mad2l2 protein, mouse |
| Journal Title: | Nature |
| Volume: | 430 |
| Issue: | 7001 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2004-08-12 |
| Start Page: | 797 |
| End Page: | 802 |
| Language: | English |
| DOI: | 10.1038/nature02820 |
| PROVIDER: | scopus |
| PUBMED: | 15306814 |
| DOI/URL: | |
| Notes: | Nature -- Cited By (since 1996):336 -- Export Date: 16 June 2014 -- CODEN: NATUA -- Source: Scopus |
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