Nrf2 negatively regulates melanogenesis by modulating PI3K/Akt signaling

Jung-Min Shin; Mi Yoon Kim; Kyung-Cheol Sohn; So-Young Jung; Hae-Eul Lee; Jae Woo Lim; Sooil Kim; Young-Ho Lee; Myung Im; Young-Joon Seo; Chang Deok Kim; Jeung-Hoon Lee; Young Lee; Tae-Jin Yoon

doi:10.1371/journal.pone.0096035

Nrf2 negatively regulates melanogenesis by modulating PI3K/Akt signaling

PLoS One. 2014 Apr 24;9(4):e96035. doi: 10.1371/journal.pone.0096035. eCollection 2014.

Authors

Affiliations

¹ Department of Dermatology and Research Institute for Medical Sciences, School of Medicine, Chungnam National University, Daejeon, Korea.
² Department of Anatomy, School of Medicine, Chungnam National University, Daejeon, Korea.
³ Department of Dermatology and Institute of Health Sciences, School of Medicine, Gyeongsang National University, Jinju, Korea.

Abstract

Nrf2 plays a role in protection of cells against oxidative stress and xenobiotic damage by regulating cytoprotective genes. In this study, we investigated the effect of Nrf2 on melanogenesis in normal human melanocytes (NHMCs). When NHMCs were transduced with a recombinant adenovirus expressing Nrf2, melanin synthesis was significantly decreased. Consistent with this result, overexpression of Nrf2 decreased the expression of tyrosinase and tyrosinase-related protein 1. The inhibitory effect of Nrf2 was reversed by overexpression of Keap1, an intracellular regulator of Nrf2. Interestingly, Nrf2 overexpression resulted in marked activation of PI3K/Akt signaling. Conversely, inhibition of PI3K activity by treatment with wortmannin reversed the depigmentary effects of Nrf2. Taken together, these results strongly suggest that Nrf2 negatively regulates melanogenesis by modulating the PI3K/Akt signaling pathway.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenoviridae / genetics
Androstadienes / pharmacology
Cells, Cultured
Humans
Intracellular Signaling Peptides and Proteins / metabolism
Kelch-Like ECH-Associated Protein 1
Melanins / metabolism*
Melanocytes / metabolism
Membrane Glycoproteins / metabolism
Monophenol Monooxygenase / metabolism
NF-E2-Related Factor 2 / genetics
NF-E2-Related Factor 2 / metabolism*
Oncogene Protein v-akt / metabolism*
Oxidoreductases / metabolism
Phosphatidylinositol 3-Kinases / metabolism*
Protein Kinase Inhibitors / pharmacology
Signal Transduction
Skin Pigmentation
Transduction, Genetic
Wortmannin

Substances

Androstadienes
Intracellular Signaling Peptides and Proteins
KEAP1 protein, human
Kelch-Like ECH-Associated Protein 1
Melanins
Membrane Glycoproteins
NF-E2-Related Factor 2
NFE2L2 protein, human
Protein Kinase Inhibitors
Oxidoreductases
TYRP1 protein, human
Monophenol Monooxygenase
Phosphatidylinositol 3-Kinases
Oncogene Protein v-akt
Wortmannin

Grants and funding

This work was supported by Amorepacific research fund, 2011. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of manuscript.