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Tumor suppressor functions for the Cdk inhibitor p21 in the mouse colon

Aleksandra Jovanovic Poole1, Darien Heap, Robert E Carroll

  • 1Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.

Oncogene
|September 21, 2004
PubMed

Insights

Mice lacking the Cdk inhibitor p21 showed increased susceptibility to colon cancer. Reduced apoptosis in p21-deficient mice promoted aberrant crypt foci formation, suggesting a tumor suppressor role for p21 in the colon.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • The Cdk inhibitor p21 is involved in p53-mediated growth arrest after DNA damage.
  • p21 is expressed during epithelial differentiation in organs like the colon.
  • Its role in colon cancer development, particularly concerning apoptosis, is not fully understood.

Purpose of the Study:

  • To investigate the role of p21 in colon cancer susceptibility using p21-deficient mice.
  • To determine the effect of p21 deficiency on the formation of aberrant crypt foci (ACF) induced by azoxymethane (AOM).
  • To explore the impact of p21 on apoptosis and proliferation in the colon following carcinogen exposure.

Main Methods:

  • Utilized p21-deficient and wild-type mice.
  • Administered the colon carcinogen azoxymethane (AOM) to induce aberrant crypt foci (ACF).
  • Assessed ACF formation, lymphoid aggregates, cell proliferation, and apoptosis in the colon.

Main Results:

  • p21-deficient mice developed significantly more ACF than wild-type mice after AOM treatment.
  • ACF in p21-deficient mice were not restricted to the distal colon.
  • AOM-induced apoptosis was observed in wild-type mice but not in p21-deficient mice, while proliferation rates were similar.
  • Increased lymphoid aggregates were noted in p21-deficient colons post-AOM.

Conclusions:

  • p21 deficiency enhances susceptibility to AOM-induced colon tumorigenesis, supporting a tumor suppressor role for p21 in the colon.
  • Reduced apoptosis of colon epithelial cells with mutations may initiate ACF formation.
  • The proapoptotic function of p21 in this context was unexpected, contrasting its known anti-apoptotic roles in other systems.

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