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Ionizing radiation down-regulates p53 protein in primary Egr-1-/- mouse embryonic fibroblast cells causing enhanced

A Das1, D Chendil, S Dey

  • 1Department of Radiation Medicine and Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536, USA.

The Journal of Biological Chemistry
|October 18, 2000
PubMed

Insights

Early growth response-1 (Egr-1) and p53 protein are crucial for radiation-induced apoptosis. Egr-1 regulates p53 stability via Rb protein, preventing MDM2-mediated degradation and promoting cell death.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The transcription factor Early Growth Response-1 (Egr-1) plays a role in cellular responses to stress.
  • p53 is a critical tumor suppressor protein involved in apoptosis and cell cycle arrest.
  • Understanding the interplay between Egr-1 and p53 is vital for cancer therapy.

Purpose of the Study:

  • To elucidate the mechanism by which Egr-1 promotes apoptosis in relation to p53 status.
  • To investigate the role of Egr-1 in regulating p53 stability and function after ionizing radiation.
  • To determine the involvement of Rb protein in the Egr-1-mediated apoptotic pathway.

Main Methods:

  • Primary mouse embryonic fibroblast (MEF) cells from Egr-1 knock-out mice (homozygous and heterozygous) were utilized.
  • Cells were exposed to ionizing radiation to assess apoptosis and protein levels.
  • Western blotting, p53-CAT activity assays, and co-immunoprecipitation were performed.

Main Results:

  • Ionizing radiation induced significantly higher apoptosis in Egr-1 heterozygous cells compared to homozygous cells.
  • Egr-1 heterozygous cells showed elevated p53 protein and activity post-radiation, while Egr-1 homozygous cells exhibited p53 degradation.
  • Egr-1 overexpression in p53-null MEF cells showed marginal induction of apoptosis.
  • Egr-1 deficiency led to reduced Rb levels and increased p53-MDM2 complex formation, facilitating p53 degradation.

Conclusions:

  • Egr-1 transregulates p53, and both are essential for radiation-induced apoptosis.
  • Egr-1's proapoptotic function is mediated by Rb protein, which counteracts MDM2-mediated p53 degradation.
  • The Egr-1-Rb-MDM2-p53 axis is critical for controlling apoptosis in response to DNA damage.

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