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H-, K- and N-Ras inhibit myeloid leukemia cell proliferation by a p21WAF1-dependent mechanism

M D Delgado1, J P Vaqué, I Arozarena

  • 1Grupo de Biología Molecular del Cáncer, Departamento de Biología Molecular y Unidad Asociada al Centro de Investigaciones Biológicas (CSIC), Universidad de Cantabria, Santander, Spain.

Oncogene
|March 4, 2000
PubMed

Insights

Ras genes, common in cancer, inhibit primary cell growth via p53 and cell cycle inhibitors. This study shows ras also inhibits leukemia cell growth by inducing p21WAF1, independent of p53, p16INK4a, and p19ARF.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Mutated ras genes are prevalent in human cancers.
  • Oncogenic ras typically inhibits primary cell growth through p53 and cell cycle inhibitors (p16INK4a, p19ARF).
  • K562 leukemia cells are deficient in p53, p16INK4a, p15INK4b, and p19ARF.

Purpose of the Study:

  • To investigate the effect of ectopic expression of wild-type and oncogenic ras genes on K562 leukemia cell proliferation.
  • To elucidate the role of p21WAF1 in ras-mediated growth inhibition in these cells.
  • To determine if ras-mediated growth inhibition is dependent on p53, p16INK4a, or p19ARF in this cellular context.

Main Methods:

  • Ectopic expression of wild-type and oncogenic H-, K-, and N-ras in K562 cells.
  • Analysis of cell proliferation and clonogenic growth.
  • Measurement of p21WAF1 mRNA and protein levels.
  • Reporter assays to assess p21WAF1 promoter activity.
  • Use of antisense constructs to inhibit p21WAF1 expression.

Main Results:

  • Both wild-type and oncogenic ras genes inhibited the clonogenic growth of K562 cells.
  • Expression of oncogenic H-rasV12 led to growth retardation, accompanied by increased p21WAF1 mRNA and protein.
  • Ras, particularly oncogenic ras, potently activated the p21WAF1 promoter in a p53-independent manner.
  • Inhibition of p21WAF1 expression partially reversed the growth inhibitory effects of oncogenic H-ras.

Conclusions:

  • Ras-mediated antiproliferative effects in myeloid leukemia cells are linked to the induction of p21WAF1 expression.
  • These findings suggest the existence of p16INK4a and p19ARF-independent pathways for ras-mediated growth inhibition.
  • The study highlights a novel mechanism of ras signaling in leukemia cells lacking key tumor suppressors.

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