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Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention

J D Hayes1, M McMahon

  • 1Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK. hayes@icrf.icnet.uk

Cancer Letters
|November 2, 2001
PubMed

Insights

Cancer chemopreventive agents boost detoxifying and antioxidant genes by activating the Nrf1 and Nrf2 pathway. This mechanism involves transcription factors moving to the nucleus to induce protective gene expression via the antioxidant responsive element (ARE).

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Cancer chemopreventive blocking agents are known to enhance the expression of crucial detoxication and antioxidant genes.
  • These genes play a vital role in cellular defense against carcinogens and oxidative stress.

Purpose of the Study:

  • To provide an overview of the molecular mechanisms underlying gene induction by cancer chemopreventive agents.
  • To elucidate the role of specific transcription factors and signaling pathways in this process.

Main Methods:

  • The study reviews existing literature on gene expression regulation.
  • Focuses on the antioxidant responsive element (ARE) and its associated transcription factors, Nrf1 and Nrf2.
  • Discusses the role of Keap1 in regulating Nrf1/Nrf2 activity and the involvement of protein kinases.

Main Results:

  • Cancer chemopreventive agents transcriptionally activate a gene battery including NAD(P)H:quinone oxidoreductase, glutathione S-transferases, and heme oxygenase.
  • Gene induction is mediated by the antioxidant responsive element (ARE), dependent on Nuclear Factor-Erythroid 2p45-related factors (Nrf1 and Nrf2).
  • Nrf1 and Nrf2 translocate to the nucleus upon induction, forming heterodimers with other transcription factors to bind the ARE.

Conclusions:

  • The Nrf1/Nrf2 pathway, regulated by Keap1, is central to the chemopreventive effects of blocking agents.
  • Understanding these molecular mechanisms can inform the development of novel cancer prevention strategies.
  • Protein kinases are implicated in signal transduction pathways leading to ARE-mediated gene induction.

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