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Oncogenic aberrations of p16INK4/CDKN2 and cyclin D1 cooperate to deregulate G1 control

J Lukas1, L Aagaard, M Strauss

  • 1Danish Cancer Society, Division of Cancer Biology, Copenhagen O, Denmark.

Cancer Research
|November 1, 1995
PubMed

Insights

Abnormalities in cyclin D1 and p16INK4/CDKN2 (cyclin-dependent kinase inhibitor 2A) cooperate to affect cell cycle control in cancer. These upstream pathway defects contribute to multistep tumorigenesis, especially in retinoblastoma-positive cells.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Genetics

Background:

  • The G1 regulatory pathway, involving p16INK4/CDKN2, D-type cyclins, cyclin-dependent kinases, and retinoblastoma protein (RB), is crucial for cell cycle control and frequently altered in cancer.
  • Understanding the interplay between these components is vital for deciphering oncogenesis.

Purpose of the Study:

  • To investigate the concurrent alterations in the G1 regulatory pathway components, specifically cyclin D1 and p16INK4/CDKN2, in cancer.
  • To elucidate the functional consequences of these concurrent alterations on cell cycle regulation and cancer cell growth.

Main Methods:

  • Analysis of cancer cell lines for abnormalities in cyclin D1 and p16INK4/CDKN2.
  • Gene and protein transfer experiments in diploid fibroblasts and cancer cells (RB-positive and RB-deficient).

Main Results:

  • Approximately two-thirds of cancer cell lines with cyclin D1 aberrations also showed concomitant p16INK4/CDKN2 abnormalities.
  • Concurrent alterations in cyclin D1 and p16 levels were shown to cooperate in regulating G1 control in diploid fibroblasts.
  • These combined alterations influenced the growth of retinoblastoma (RB)-positive cancer cells but not RB-deficient ones.

Conclusions:

  • The biological impact of deregulating individual G1 pathway components is unequal, reflecting their hierarchical roles.
  • While RB loss completely abolishes the G1 checkpoint, upstream defects in cyclin D1 and p16INK4/CDKN2 can cooperate during multistep tumorigenesis.
  • These findings highlight the cooperative role of upstream G1 regulators in cancer development.

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