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Increased p21 expression and complex formation with cyclin E/CDK2 in retinoid-induced pre-B lymphoma cell apoptosis

George C Bao1, Jian-Guang Wang, Ambrose Jong

  • 1Division of Hematology/Oncology, Childrens Hospital Los Angeles Saban Research Institute, Los Angeles, CA 90027, USA.

FEBS Letters
|June 13, 2006
PubMed

Insights

Retinoic acid (RA) induces lymphoma cell death by upregulating p21, a cyclin-dependent kinase (CDK) inhibitor. This p21 upregulation diverts CDK2 from proliferation to apoptosis, revealing a novel RA signaling pathway.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Cip/Kip protein p21 acts as a cyclin-dependent kinase (CDK) inhibitor.
  • Retinoic acid receptor alpha (RARalpha) directly transactivates p21 upon retinoic acid (RA) binding.
  • The function of RA-induced p21 upregulation in lymphoma remains unclear.

Purpose of the Study:

  • To investigate the role of p21 upregulation by RA in human pre-B lymphoma Nalm6 cells.
  • To elucidate the mechanism by which RA inhibits lymphoma cell proliferation.

Main Methods:

  • Treatment of Nalm6 cells with RA.
  • Analysis of cell death, apoptosis markers (caspase-3 activation), and protein complex formation (p21 with cyclin E/CDK2).
  • Assessment of cyclin E and CDK2 protein levels.

Main Results:

  • RA induced proliferation inhibition in Nalm6 cells, characterized by massive apoptosis.
  • RA-induced p21 upregulation preceded and accompanied caspase-3 activation.
  • p21 formed complexes with cyclin E/CDK2, while cyclin E and CDK2 levels remained constant.
  • CDK2's function was diverted from proliferation to apoptosis promotion.

Conclusions:

  • RA induces apoptosis in lymphoma cells via p21 upregulation.
  • p21/cyclin E/CDK2 complex formation is a key event in RA-induced apoptosis.
  • A novel RA signaling pathway exists where p21 diverts CDK2 function to promote apoptosis, rather than proliferation.

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