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Nrf2 negatively regulates melanogenesis by modulating PI3K/Akt signaling

Jung-Min Shin1, Mi Yoon Kim1, Kyung-Cheol Sohn1

  • 1Department of Dermatology and Research Institute for Medical Sciences, School of Medicine, Chungnam National University, Daejeon, Korea.

Plos One
|April 26, 2014
PubMed

Insights

Nuclear factor erythroid 2-related factor 2 (Nrf2) inhibits melanogenesis, the process of melanin production. Nrf2 activation decreases melanin synthesis and key enzyme expression in human melanocytes via the PI3K/Akt pathway.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Dermatology

Background:

  • Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor crucial for cellular defense against oxidative stress and xenobiotics.
  • Nrf2 regulates the expression of numerous cytoprotective genes.
  • The role of Nrf2 in melanogenesis, the process of melanin pigment production, is not well understood.

Purpose of the Study:

  • To investigate the effect of Nrf2 on melanogenesis in normal human melanocytes (NHMCs).
  • To elucidate the molecular mechanisms underlying Nrf2's influence on melanin synthesis.

Main Methods:

  • Normal human melanocytes (NHMCs) were transduced with a recombinant adenovirus expressing Nrf2.
  • Expression levels of melanogenesis-related genes (tyrosinase, tyrosinase-related protein 1) were analyzed.
  • The role of Keap1, an Nrf2 regulator, was assessed.
  • PI3K/Akt signaling pathway activation was investigated using wortmannin, a PI3K inhibitor.

Main Results:

  • Overexpression of Nrf2 in NHMCs led to a significant decrease in melanin synthesis.
  • Nrf2 overexpression reduced the expression of tyrosinase and tyrosinase-related protein 1.
  • The inhibitory effect of Nrf2 on melanogenesis was reversed by Keap1 overexpression.
  • Nrf2 overexpression activated the PI3K/Akt signaling pathway.
  • Inhibition of PI3K activity with wortmannin reversed the depigmentary effects of Nrf2.

Conclusions:

  • Nrf2 negatively regulates melanogenesis in normal human melanocytes.
  • Nrf2 exerts its depigmentary effects by modulating the PI3K/Akt signaling pathway.
  • These findings identify Nrf2 as a potential target for modulating skin pigmentation.

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