Attenuation of UVB-Induced Sunburn Reaction and Oxidative DNA Damage with no Alterations in UVB-Induced Skin Carcinogenesis in Nrf2 Gene-Deficient Mice

Kawachi, Yasuhiro; Xu, Xuezhu; Taguchi, Shiroma; Sakurai, Hideko; Nakamura, Yasuhiro; Ishii, Yoshiyuki; Fujisawa, Yasuhiro; Furuta, Junichi; Takahashi, Takenori; Itoh, Ken; Yamamoto, Masayuki; Yamazaki, Fumikazu; Otsuka, Fujio

doi:10.1038/sj.jid.5701245

Cited by 73 publications

(54 citation statements)

References 36 publications

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“…Increased Nrf2-mediated gene expression in all layers of the epidermis strongly reduced the rate of UVB-induced apoptosis. This is in line with the UVprotective effect of broccoli sprout extracts (DinkovaKostova et al 2006), and with the enhanced UVB-induced apoptosis in ear skin keratinocytes of Nrf2 knockout mice (Kawachi et al 2008). As the mechanism underlying the UVB-protective effect of caNrf2, we identified Nrf2-mediated reduction of oxidative stress through enhanced expression of ROS-detoxifying enzymes and increased synthesis of GSH.…”

Section: Discussionsupporting

confidence: 57%

“…Recent results even indicated repression of Nrf2 activity by high UVB doses in normal human keratinocytes (Marrot et al 2008;Kokot et al 2009). The basal activity of Nrf2 seems to be required for protection of keratinocytes from UV cytotoxicity, since Nrf2 knockout mice showed a higher rate of apoptosis and oxidative damage in ear skin keratinocytes after UVB irradiation (Kawachi et al 2008). Vice versa, topical treatment of SKH-1 mouse back skin with broccoli sprout extracts that contain the Nrf2 activator sulforaphane protected against UVB-induced photocarcinogenesis (Dinkova-Kostova et al 2006).…”

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confidence: 99%

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Nrf2 establishes a glutathione-mediated gradient of UVB cytoprotection in the epidermis

Schäfer¹,

Dütsch²,

Keller³

et al. 2010

Genes Dev.

148

165

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Ultraviolet (UV) B irradiation can severely damage the skin and even induce tumorigenesis. It exerts its effects by direct DNA modification and by formation of reactive oxygen species (ROS). We developed a strategy to genetically activate target gene expression of the transcription factor NF-E2-related factor 2 (Nrf2) in keratinocytes in vivo based on expression of a constitutively active Nrf2 mutant. Activation of Nrf2 target genes strongly reduced UVB cytotoxicity through enhancement of ROS detoxification. Remarkably, the protective effect was extended to neighboring cells. Using different combinations of genetically modified mice, we demonstrate that Nrf2 activates the production, recycling, and release of glutathione and cysteine by suprabasal keratinocytes, resulting in protection of basal cells in a paracrine, glutathione/cysteine-dependent manner. Most importantly, we found that endogenous Nrf2 controls selective protection of suprabasal keratinocytes from UVB-induced apoptosis through activation of cytoprotective genes. This finding explains the preferential UVB-induced apoptosis of basal cells, which is important for elimination of mutated stem cells as well as for preservation of skin integrity. Taken together, our results identify Nrf2 as a key regulator in the UV response of the skin.[Keywords: Apoptosis; Nrf2; UVB; reactive oxygen species; glutathione] Supplemental material is available at http://www.genesdev.org.

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Section: Discussionsupporting

confidence: 57%

mentioning

confidence: 99%

Nrf2 establishes a glutathione-mediated gradient of UVB cytoprotection in the epidermis

Schäfer¹,

Dütsch²,

Keller³

et al. 2010

Genes Dev.

148

165

View full text Add to dashboard Cite

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“…In summary, our findings demonstrate that cinnamoyl-based Nrf2-activators may serve as potent antagonists of 1 O 2 -induced photo-oxidative stress in cultured human skin cells suggesting a potential use of these prototype agents as skin photo-chemopreventive factors [29,[39][40][41]47]. Future studies must evaluate the photoprotective performance of cinnamoylbased and other Nrf2-activators as a function of solar spectral range (UVB, UVA, visible) in acute (sunburn) and chronic models of skin photodamage in appropriate animal models in order to define their potential use as combinatorial photoprotective ingredients [29].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, recent studies strongly suggest a role of Nrf2-mediated gene expression in the suppression of acute photo-oxidative damage in skin cells and also in the prevention of epidermal chemical (TPA/DMBA-induced) and UVinduced carcinogenesis [37][38][39]. In the skin of Nrf2 knockout mice, UVB-irradiation induced a more pronounced sunburn reaction and oxidative DNA damage as compared to wildtype mice, but no alterations in UVB-induced carcinogenesis were observed [40]. However, pharmacological induction of Nrf2 by the chemopreventive activator sulforaphane has been demonstrated to protect retinal pigment epithelial cells against photo-oxidative damage by upregulating NQO1 expression and elevating cellular glutathione content [39].…”

Section: Introductionmentioning

confidence: 99%

Cinnamoyl-based Nrf2-activators targeting human skin cell photo-oxidative stress

Wondrak¹,

Cabello²,

Villeneuve³

et al. 2008

Free Radical Biology and Medicine

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Strong experimental evidence suggests the involvement of photo-oxidative stress mediated by reactive oxygen species as a crucial mechanism of solar damage relevant to human skin photoaging and photocarcinogenesis. Based on the established role of antioxidant response element (ARE)-mediated gene expression in cancer chemoprevention, we tested the hypothesis that small molecule Nrf2-activators may serve a photo-chemopreventive role by targeting skin cell photo-oxidative stress. A luciferase-based reporter gene assay was used as a primary screen for the identification of novel agents that modulate the Nrf2-Keap1 signaling pathway. A series of cinnamoyl-based electrophilic Michael acceptors including cinnamic aldehyde and methyl-1-cinnamoyl-5-oxo-2-pyrrolidine-carboxylate was identified as potent Nrf2-activators. Hit confirmation was performed in a secondary screen, based on immunodetection of Nrf2 protein upregulation in human Hs27 skin fibroblasts, HaCaT keratinocytes, and primary skin keratinocytes. Bioefficacy profiling of positive test compounds in skin cells demonstrated compound-induced upregulation of hemeoxygenase I and NAD(P)H-quinone oxidoreductase, two Nrf2 target genes involved in the cellular antioxidant response. Pretreatment with cinnamoylbased Nrf2-activators suppressed intracellular oxidative stress and protected against photooxidative induction of apoptosis in skin cells exposed to high doses of singlet oxygen. Our pilot studies suggest feasibility of developing cinnamoyl-based Nrf2-activators as novel photochemopreventive agents targeting skin cell photo-oxidative stress.

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“…Indeed, HO-1 null cells have been reported to be more sensitive to oxidative stress (37)(38)(39)(40)(41), and Bach1-overexpressing cells share certain features with Nrf2-deficient cells, which show high levels of cell death upon oxidative stress (42)(43)(44), suggesting that Bach1 overexpression predisposes cells to oxidative stress. Bach1 activity is negatively controlled through multiple mechanisms, including inhibition of DNA binding, induction of nuclear export, and degradation through the polyubiquitination pathway (7,29).…”

Section: Discussionmentioning

confidence: 99%

Bach1-dependent and -independent Regulation of Heme Oxygenase-1 in Keratinocytes

Okada

Muto

Ogawa

et al. 2010

Journal of Biological Chemistry

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Bach1 is a member of the basic leucine zipper transcription factor family, and the Bach1/small Maf heterodimer specifically represses transcriptional activity directed by the Maf recognition element (MARE). Because Bach1 is a repressor of the oxidative stress response, we examined the function(s) of Bach1 in keratinocytes subjected to oxidative stress. Oxidative stress induced by H 2 O 2 led to an increase in MARE activity and expression of heme oxygenase-1 (HO-1), an inducible antioxidant defense enzyme. Bach1 depletion by small interfering RNAs or by deletion of Bach1 enhanced HO-1 expression in the absence of H 2 O 2 , indicating that Bach1 is a critical repressor of HO-1 in keratinocytes. Although Bach1-deficient or -reduced keratinocytes expressed higher levels of HO-1 than control cells in response to H 2 O 2 , Bach1 down-regulation did not attenuate the production of reactive oxygen species by H 2 O 2 . In contrast, Bach1 overexpression abolished HO-1 induction by H 2 O 2 , which led to increased reactive oxygen species accumulation. HO-1 was induced during keratinocyte differentiation, but MARE activity did not change during differentiation. Furthermore, Bach1 overexpression did not inhibit differentiation-associated induction of HO-1 expression, suggesting that HO-1 induction in differentiation is independent of Bach1. Thus, in response to oxidative stress, Bach1 regulates the oxidation state through the negative control of HO-1 expression prior to terminal keratinocyte differentiation. However, Bach1-mediated repression is negated during keratinocyte differentiation.Redox regulation is critical to cell survival, because cells cannot avoid endogenous reactive oxygen species (ROS) 2 that are generated as by-products of respiration (1). The skin is constantly exposed to harmful ROS that are generated by prooxidant agents in the environment, as well as by endogenous cellular oxidants. Thus, keratinocytes strongly and constitutively express ROS-detoxifying enzymes, including superoxide dismutase, catalase, glutathione peroxidase, and reductase, and contain substantial levels of the antioxidants tocopherol and ubiquinol (2, 3). Additionally, these cells possess an inducible defense system that includes heme oxygenase-1 (HO-1) (3-5). An imbalance between ROS and antioxidants can lead to the generation of high oxidant levels, which play a pivotal role in skin aging and disease (6).The transcription factor Bach1 is a repressor of the oxidative stress response in higher eukaryotes (7,8) and, together with its paralogue Bach2, constitutes a subfamily of the basic leucine zipper family of proteins. Bach1 forms heterodimers with the basic leucine zipper subfamily of small Maf proteins (i.e. MafF, MafG, and MafK), which bind the Maf recognition element (MARE) in the promoter regions of genes such as HO-1, NADP(H) quinone (oxido)reductase, and ␤-globin (7, 9, 10), and thereby repress transcription in the absence of oxidative stress. In the presence of oxidative stress, Bach1 is inactivated (11, 12), which allows tran...

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Attenuation of UVB-Induced Sunburn Reaction and Oxidative DNA Damage with no Alterations in UVB-Induced Skin Carcinogenesis in Nrf2 Gene-Deficient Mice

Cited by 73 publications

References 36 publications

Nrf2 establishes a glutathione-mediated gradient of UVB cytoprotection in the epidermis

Nrf2 establishes a glutathione-mediated gradient of UVB cytoprotection in the epidermis

Cinnamoyl-based Nrf2-activators targeting human skin cell photo-oxidative stress

Bach1-dependent and -independent Regulation of Heme Oxygenase-1 in Keratinocytes

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