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Effect of p21waf1/cip1 transgene on radiation induced apoptosis in T cells

R Fotedar1, H Brickner, N Saadatmandi

  • 1Institut de Biologie Structurale JP Ebel, Grenoble, France.

Oncogene
|June 25, 1999
PubMed

Insights

The cyclin-dependent kinase inhibitor p21 enhances p53-dependent apoptosis in thymocytes. Increased p21 levels make T cells more sensitive to DNA damage-induced cell death, but this effect requires functional p53.

Area of Science:

  • Cell biology
  • Molecular biology
  • Immunology

Background:

  • The tumor suppressor p53 upregulates the cyclin-dependent kinase inhibitor p21WAF1/Cip1.
  • p21 is crucial for p53-mediated G1 arrest.
  • The role of p21 in p53-dependent apoptosis remains unclear.

Purpose of the Study:

  • To investigate the physiological role of p21 in apoptosis.
  • To determine if p21 functions as a downstream effector of p53-dependent apoptosis.

Main Methods:

  • Generated transgenic mice with restricted p21 expression in the T cell lineage.
  • Exposed thymocytes from transgenic and control mice to DNA damaging agents (ionizing radiation, UV) and dexamethasone.
  • Assessed cell death and apoptosis levels.
  • Utilized p53-/- mice and p21 + Bcl2 + double transgenic mice.

Main Results:

  • Thymocytes from p21 transgenic mice showed hypersensitivity to cell death induced by ionizing radiation and UV, but not dexamethasone.
  • Irradiated p21 transgenic thymocytes exhibited approximately twofold more apoptotic cells compared to controls.
  • Bcl2 transgene expression rescued the radiation hypersensitivity in p21 transgenic thymocytes.
  • Thymocytes from p53-/- mice, even with p21 transgene expression, were resistant to radiation-induced death.

Conclusions:

  • Thymocytes from p21 transgenic mice are hypersensitive to radiation-induced programmed cell death.
  • This hypersensitivity involves a p53-dependent pathway and signals beyond p21 itself.

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