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Inhibitors of cyclin-dependent kinase and cancer

J R Biggs1, A S Kraft

  • 1L.B. Wallace Tumor Institute, University of Alabama at Birmingham, 35294-3300, USA.

Journal of Molecular Medicine (Berlin, Germany)
|October 1, 1995
PubMed

Insights

Oncogenesis disrupts cell cycle regulation proteins, particularly cyclin-dependent kinase (CDK) inhibitors like p16. While p16 mutations are common in tumors, p21/WAF1/Cip1 absence correlates with transformation but lacks mutations.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Cell cycle regulation is crucial for preventing uncontrolled cell growth.
  • Oncogenesis involves disruptions in cell cycle control mechanisms.
  • Proteins that regulate cyclin-dependent kinases (CDKs) are key players in cell cycle progression.

Purpose of the Study:

  • To explore the connections between oncogenesis and cell cycle regulatory proteins.
  • To identify classes of proteins targeted for inactivation during cancer development.
  • To investigate the roles of CDK inhibitors (p16, p21/WAF1/Cip1, p27Kip) and regulatory kinases/phosphatases in cancer.

Main Methods:

  • Review of recent research on oncogenesis and cell cycle proteins.
  • Analysis of mutation data for p16 in tumor cell lines and primary tumors.
  • Examination of correlations between p21/WAF1/Cip1 absence and cellular transformation.
  • Identification of kinases and phosphatases regulating CDK activity as potential oncogenic targets.

Main Results:

  • Three classes of CDK inhibitory proteins are potential targets for oncogenic inactivation.
  • p16 is frequently mutated in tumor cell lines and some primary tumors, affecting G1 to S phase transition.
  • p21/WAF1/Cip1 and p27Kip inhibit a wider range of cyclin/CDK complexes.
  • Absence of p21/WAF1/Cip1 correlates with cellular transformation, but no mutations are found in tumors.
  • Kinases and phosphatases regulating CDK activity are also potential targets for oncogenic inactivation.

Conclusions:

  • Disruption of cell cycle regulatory proteins, including CDK inhibitors and regulators, is a hallmark of oncogenesis.
  • Specific alterations in p16 are linked to cancer development.
  • While p21/WAF1/Cip1's absence is associated with transformation, its role may differ from direct mutation.
  • Loss of regulation in CDK activity due to genetic alterations in these proteins can lead to uncontrolled cell growth and cancer.

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