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p15Ink4b is a critical tumour suppressor in the absence of p16Ink4a

Paul Krimpenfort1, Annemieke Ijpenberg, Ji-Ying Song

  • 1Division of Molecular Genetics and Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.

Nature
|August 24, 2007
PubMed

Insights

The complete CDKN2b-CDKN2a locus deletion in mice leads to increased tumor susceptibility and a broader range of cancers. This suggests p15INK4b acts as a backup for p16INK4a, explaining locus loss in human tumors.

Area of Science:

  • Cancer Biology
  • Genetics
  • Cell Cycle Regulation

Background:

  • The CDKN2b-CDKN2a locus on chromosome 9p21 is frequently lost in human cancers.
  • This locus encodes three cell cycle inhibitors: p15INK4b, p16INK4a, and p14ARF.
  • The tumor suppressor roles of p16INK4a and p14ARF are established, but p15INK4b's function is unclear.

Purpose of the Study:

  • To investigate the role of p15INK4b in tumor suppression.
  • To determine if combined deficiency of p15INK4b, p14ARF, and p16INK4a has synergistic effects on tumor development.
  • To explore the potential backup function of p15INK4b for p16INK4a.

Main Methods:

  • Generation of mice deficient for all three open reading frames (Cdkn2ab-/-).
  • Comparison of tumor development in Cdkn2ab-/- mice versus Cdkn2a mutant mice.
  • Analysis of oncogenic transformation sensitivity in mouse embryonic fibroblasts (MEFs).

Main Results:

  • Cdkn2ab-/- mice exhibited increased tumor proneness and a wider spectrum of tumors compared to Cdkn2a mutants.
  • Skin tumors and soft tissue sarcomas, often with mixed cell types and biphasic differentiation, were prevalent in Cdkn2ab-/- mice.
  • Cdkn2ab-/- MEFs were significantly more sensitive to oncogenic transformation than Cdkn2a mutant MEFs.
  • p15Ink4b protein levels increased under stress in p16Ink4a-deficient MEFs.

Conclusions:

  • p15INK4b plays a critical backup role for p16INK4a's tumor suppressor function.
  • The combined deficiency of p15INK4b, p14ARF, and p16INK4a contributes to increased tumorigenesis.
  • These findings explain the frequent deletion of the entire CDKN2b-CDKN2a locus in human tumors.

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