The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling

Nat Cell Biol. 2001 Dec;3(12):1124-8. doi: 10.1038/ncb1201-1124.

Abstract

The PTEN tumour suppressor and pro-apoptotic gene is frequently mutated in human cancers. We show that PTEN transcription is upregulated by Egr-1 after irradiation in wild-type, but not egr-1-/-, mice in vivo. We found that Egr-1 specifically binds to the PTEN 5' untranslated region, which contains a functional GCGGCGGCG Egr-1-binding site. Inducing Egr-1 by exposing cells to ultraviolet light upregulates expression of PTEN messenger RNA and protein, and leads to apoptosis. egr-1-/- cells, which cannot upregulate PTEN expression after irradiation, are resistant to ultraviolet-light-induced apoptosis. Therefore, Egr-1 can directly regulate PTEN, triggering the initial step in this apoptotic pathway. Loss of Egr-1 expression, which often occurs in human cancers, could deregulate the PTEN gene and contribute to the radiation resistance of some cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Apoptosis / radiation effects
  • Cells, Cultured
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Dermis / cytology
  • Early Growth Response Protein 1
  • Etoposide / pharmacology
  • Fibroblasts / cytology
  • Gamma Rays
  • Gene Expression Regulation, Neoplastic / physiology
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Humans
  • Immediate-Early Proteins*
  • Mammary Glands, Animal / cytology
  • Mice
  • Mice, Knockout
  • Neoplasms / physiopathology
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • PTEN Phosphohydrolase
  • Phosphoric Monoester Hydrolases / genetics*
  • Phosphoric Monoester Hydrolases / metabolism*
  • Promoter Regions, Genetic / genetics
  • RNA, Messenger / analysis
  • Signal Transduction / physiology
  • Signal Transduction / radiation effects*
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism*
  • Ultraviolet Rays

Substances

  • DNA-Binding Proteins
  • EGR1 protein, human
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Immediate-Early Proteins
  • Nucleic Acid Synthesis Inhibitors
  • RNA, Messenger
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Etoposide
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human