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Regulation of Nrf2 transactivation domain activity by p160 RAC3/SRC3 and other nuclear co-regulators

Wen Lin1, Guoxiang Shen, Xiaoling Yuan

  • 1Department of Pharmaceutics, Ernest-Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, 08854, USA.

Journal of Biochemistry and Molecular Biology
|June 8, 2006
PubMed

Insights

Receptor associated coactivator 3 (RAC3/SRC3) and other nuclear co-regulators enhance the transcriptional activity of Nrf2. These co-regulators, including CBP/p300, CARM1, PRMT1, and p/CAF, show synergistic effects with RAC3/SRC3 in activating Nrf2 transactivation.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Gene Regulation

Background:

  • Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor crucial for cellular defense against oxidative stress and detoxification.
  • Nrf2 regulates the expression of Phase II detoxifying and antioxidant enzymes, playing a vital role in cancer chemoprevention.
  • Understanding the co-regulators involved in Nrf2 transcriptional activation is essential for developing targeted cancer therapies.

Purpose of the Study:

  • To investigate the role of receptor associated coactivator 3 (RAC3/SRC3) in the transcriptional activation of Nrf2.
  • To examine the involvement of other nuclear co-regulators, including CBP/p300, CARM1, PRMT1, and p/CAF, in Nrf2 transactivation.
  • To determine the synergistic effects of RAC3/SRC3 with other co-regulators on Nrf2 transcriptional activity.

Main Methods:

  • Utilized a chimeric Gal4-Nrf2-Luciferase system in HepG2 cells to assess Nrf2 transactivation.
  • Investigated the dose-dependent effect of RAC3/SRC3 on the transactivation domain (TAD) of Nrf2.
  • Examined the impact of dominant-negative RAC3 mutants on Nrf2 transactivation.
  • Assessed the individual and combined effects of CBP/p300, CARM1, PRMT1, and p/CAF on Nrf2 TAD activity.

Main Results:

  • RAC3/SRC3 significantly up-regulated the transactivation activity of the Nrf2 TAD in a dose-dependent manner.
  • Dominant-negative RAC3 mutants diminished the enhancement of Nrf2 TAD activity by RAC3.
  • CBP/p300, CARM1, PRMT1, and p/CAF demonstrated varying degrees of positive effects on Nrf2 TAD activity.
  • Synergistic transcriptional activation of Nrf2 TAD was observed when RAC3/SRC3 was combined with other nuclear co-regulators.

Conclusions:

  • RAC3/SRC3 is a key player in the functional transactivation of the Nrf2 TAD.
  • Nuclear co-regulators CBP/p300, CARM1, PRMT1, and p/CAF can independently activate Nrf2 TAD.
  • These co-regulators can further potentiate the Nrf2 transactivation activity mediated by RAC3/SRC3, highlighting a complex regulatory network.

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