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Oncogenic Ras induces p19ARF and growth arrest in mouse embryo fibroblasts lacking p21Cip1 and p27Kip1 without

A Groth1, J D Weber, B M Willumsen

  • 1Department of Tumor Cell Biology and Howard Hughes Medical Institute, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

The Journal of Biological Chemistry
|June 8, 2000
PubMed

Insights

Oncogenic Ras triggers senescence via INK4a/ARF tumor suppressors. In cells lacking key cell cycle inhibitors, Ras promotes abnormal cell division and polyploidy, impacting cell cycle completion.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Tumor Suppressor Genes

Background:

  • Oncogenic Ras is a key driver of cellular transformation and senescence.
  • The INK4a/ARF locus encodes p16(INK4a) and p19(ARF), critical tumor suppressors.
  • p16(INK4a) inhibits cyclin D-dependent kinases, while p19(ARF) activates p53.

Purpose of the Study:

  • To investigate the role of oncogenic Ras in cell cycle regulation, particularly in the absence of specific cell cycle inhibitors.
  • To understand the interplay between Ras, INK4a/ARF, and cyclin-dependent kinase inhibitors (CKIs) in cell proliferation and transformation.

Main Methods:

  • Utilized primary human and rodent fibroblasts, including immortalized cell lines and genetically modified mouse embryo fibroblasts.
  • Examined the expression of p16(INK4a) and p19(ARF) in response to oncogenic Ras.
  • Analyzed cell cycle progression, DNA synthesis, nuclear division, cytokinesis, and ploidy in cells with varying genetic backgrounds.

Main Results:

  • Oncogenic Ras induces p16(INK4a) and p19(ARF) in normal fibroblasts, causing cell cycle arrest.
  • Cells lacking INK4a/ARF, ARF, or p53 are resistant to Ras-induced growth inhibition.
  • In fibroblasts lacking p21(Cip1) and p27(Kip1), Ras induced p19(ARF) but not p16(INK4a), leading to abnormal cell division and polyploidy instead of G1 arrest.

Conclusions:

  • p16(INK4a) and p19(ARF) are crucial mediators of Ras-induced senescence.
  • The absence of CKIs like p21(Cip1) and p27(Kip1) alters Ras's effect on the cell cycle, bypassing G1 arrest.
  • Oncogenic Ras can disrupt cell cycle completion through mechanisms independent of canonical senescence pathways when key inhibitors are absent.

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