Deficiency of Retinoblastoma gene in mouse embryonic stem cells leads to genetic instability

Lei Zheng, Andrea Flesken-Nikitin, Phang Lang Chen, Wen Hwa Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Genetic instability has been recognized as a hallmark of human cancers. Retinoblastoma (Rb) tumor suppressor protein has an essential role in modulating cell cycle progression. However, there is no direct evidence supporting its role in maintaining genetic stability. Here, we developed a sensitive method to examine the level of chromosome instability by using retrovirus carrying both positive and negative selectable markers that integrated randomly into individual chromosomes, and the frequency of loss of this selectable chromosomal marker (LOM) in normal mammalian cells was measured. Our results showed that normal mouse embryonic stem (ES) cells had a very low frequency of LOMs, which was less than 10-8/cell/generation. In Rb-/- mouse ES cells, the frequency was increased to approximately 10-5/cell/generation, whereas in Rb+/- ES cells, the frequency was approximately 10-7/cell/generation. LOMs was mediated mainly through chromosomal mechanisms and not through point mutations. These results, therefore, revealed that Rb, with a haploinsufficiency, plays a critical role in the maintenance of chromosome stability. The mystery of why Rb heterozygous carriers have early-onset tumor formation with high penetrance can be, at least, partially explained by this novel activity.

Original languageEnglish (US)
Pages (from-to)2498-2502
Number of pages5
JournalCancer Research
Volume62
Issue number9
StatePublished - May 1 2002
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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