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P21Waf1/Cip1 dysfunction in neuroblastoma: a novel mechanism of attenuating G0-G1 cell cycle arrest

Pamela P McKenzie1, Mary K Danks, Richard W Kriwacki

  • 1Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Cancer Research
|July 4, 2003
PubMed

Insights

In neuroblastoma cells, the cell cycle inhibitor p21 (Waf1/Cip1) is produced but cannot bind to cyclin-dependent kinase 2 (cdk2). This defect in p21 function impairs the G(0)-G(1) cell cycle checkpoint, promoting tumor growth.

Area of Science:

  • Molecular Biology
  • Cell Cycle Regulation
  • Oncology

Background:

  • DNA damage in normal cells activates p53, inducing p21(Waf1/Cip1).
  • p21(Waf1/Cip1) normally binds and inhibits cyclin-dependent kinase 2 (cdk2), causing G(0)-G(1) cell cycle arrest.
  • Neuroblastoma (NB) cells exhibit impaired G(0)-G(1) checkpoint despite p53 and p21 expression.

Purpose of the Study:

  • Investigate the mechanism of G(0)-G(1) checkpoint attenuation in neuroblastoma cells.
  • Determine why p21(Waf1/Cip1) fails to inhibit cdk2 activity in NB cells.
  • Explore the therapeutic potential of targeting defective cell cycle inhibitors in NB.

Main Methods:

  • Analysis of p53-p21 pathway in neuroblastoma cells.
  • Assessing p21(Waf1/Cip1) binding and inhibitory activity against cdk2 in vitro and in cell extracts.
  • Evaluating the effect of recombinant p21 protein on cdk2 activity.

Main Results:

  • Neuroblastoma cells express functional p53 and induce p21(Waf1/Cip1) expression.
  • Endogenous p21(Waf1/Cip1) in NB cells cannot bind to or inhibit cdk2 activity.
  • Recombinant p21 protein effectively inhibits cdk2 activity in NB cell extracts, indicating endogenous p21 is inactive.
  • Inactive p21 may be sequestered in a complex or adopt a non-functional conformation.

Conclusions:

  • A novel mechanism of G(0)-G(1) cell cycle arrest evasion in neuroblastoma involves dysfunctional p21(Waf1/Cip1).
  • This p21 defect may contribute to NB growth and potentially other cancers.
  • CDK inhibitors represent a potential therapeutic strategy for NB and similar tumors with defective cell cycle control.

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