Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Academic Article uri icon

Overview

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.

publication date

  • August 12, 2004

Research

keywords

  • Carrier Proteins
  • Cell Cycle
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Genomic Instability
  • Mitosis
  • Retinoblastoma Protein
  • Transcription Factors

Identity

Scopus Document Identifier

  • 4043093341

PubMed ID

  • 15306814

Additional Document Info

volume

  • 430

issue

  • 7001