The K-Ras 4A isoform promotes apoptosis but does not affect either lifespan or spontaneous tumor incidence in aging mice

Sarah J Plowman, Mark J Arends, David G Brownstein, Feijun Luo, Paul S Devenney, Lorraine Rose, Ann-Marie Ritchie, Rachel L Berry, David J Harrison, Martin L Hooper, Charles E Patek

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

Abstract

Ras proteins function as molecular switches in signal transduction pathways, and, here, we examined the effects of the K-ras4A and 4B splice variants on cell function by comparing wild-type embryonic stem (ES) cells with K-ras(tmDelta4A/tmDelta4A) (exon 4A knock-out) ES cells which express K-ras4B only and K-ras(-/-) (exons 1-3 knock-out) ES cells which express neither splice variant, and intestinal epithelium from wild-type and K-ras(tmDelta4A/tmDelta4A) mice. RT-qPCR analysis found that K-ras4B expression was reduced in K-ras(tmDelta4A/tmDelta4A) ES cells but unaffected in small intestine. K-Ras deficiency did not affect ES cell growth, and K-Ras4A deficiency did not affect intestinal epithelial proliferation. K-ras(tmDelta4A/tmDelta4A) and K-ras(-/-) ES cells showed a reduced capacity for differentiation following LIF withdrawal, and K-ras(-/-) cells were least differentiated. K-Ras4A deficiency inhibited etoposide-induced apoptosis in ES cells and intestinal epithelial cells. However, K-ras(tmDelta4A/tmDelta4A) ES cells were more resistant to etoposide-induced apoptosis than K-ras(-/-) cells. The results indicate that (1) K-Ras4A promotes apoptosis while K-Ras4B inhibits it, and (2) K-Ras4B, and possibly K-Ras4A, promotes differentiation. The findings raise the possibility that alteration of the K-Ras4A/4B isoform ratio modulates tumorigenesis by differentially affecting stem cell survival and/or differentiation. However, K-Ras4A deficiency did not affect life expectancy or spontaneous overall tumor incidence in aging mice.
Original languageEnglish
Pages (from-to)16-26
Number of pages11
JournalExperimental Cell Research
Volume312
Issue number1
DOIs
Publication statusPublished - 1 Jan 2006

Keywords

  • Aging
  • Animals
  • Apoptosis
  • Cell Differentiation
  • Cell Proliferation
  • Epithelial Cells
  • Genes, ras
  • Incidence
  • Intestine, Small
  • Longevity
  • Mice
  • Mice, Knockout
  • Neoplasms, Experimental
  • Protein Isoforms
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stem Cells

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