Skip to main content

Advertisement

SpringerLink
Log in

Nrf2-dependent and Nrf2-independent induction of phase 2 detoxifying and antioxidant enzymes during keratinocyte differentiation

  • Original Paper
  • Published:
Archives of Dermatological Research Aims and scope Submit manuscript

Abstract

As antioxidant enzymes can be actively modulated during keratinocyte (KC) differentiation, this study was aimed to evaluate the modulation of a group of phase 2 detoxifying and antioxidant enzymes (phase 2 enzymes) during KC differentiation. In postconfluence-induced differentiation model of KC, heme oxygenase-1 (HO-1), NADP(H):quinone oxidoreductase-1 (NQO-1), and glutathione S-transferase pi (GSTpi) were up-regulated at a transcriptional level. In Western blot analysis, the phase 2 enzymes were up-regulated by H2O2, but down-regulated by N-acetyl cysteine, indicating the active role of reactive oxygen species for their expression during KC differentiation. When a redox-sensitive NF-E2 related factor-2 (Nrf2), a key transcriptional factor for phase 2 enzymes, was knocked down by small interfering RNA transfection in differentiated KCs, only NQO-1 was down-regulated in both mRNA and protein levels. In human skin, expression levels of the phase 2 enzymes were up-regulated in the differentiated KC in the normal epidermis and keratotic foci in squamous cell carcinoma, further supporting the differentiation-dependent expression of phase 2 enzymes in vivo. This study demonstrates that a group of phase 2 enzymes are modulated during KC differentiation via either Nrf2-dependent (NQO-1) or Nrf2-independent (HO-1 and GSTpi) ways.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Becker JC, Fukui H, Imai Y, Sekikawa A, Kimura T, Yamagishi H, Yoshitake N, Pohle T, Domschke W, Fujimori T (2007) Colonic expression of heme oxygenase-1 is associated with a better long-term survival in patients with colorectal cancer. Scand J Gastroenterol 42:852–858

    Article  PubMed  CAS  Google Scholar 

  2. Carr WJ, Oberley-Deegan RE, Zhang Y, Oerley CC, Overley LW, Dunnwald M (2011) Antioxidant proteins and reactive oxygen species are decreased in a murine epidermal side population with stem cell-like characteristics. Histochem Cell Biol 135:293–304

    Article  PubMed  CAS  Google Scholar 

  3. Chen CY, Jang JH, Li MH, Surh YJ (2005) Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells. Biochem Biophys Res Commun 331:993–1000

    Article  PubMed  CAS  Google Scholar 

  4. Dhar A, Young MR, Colburn NH (2002) The role of AP-1, NF-κB and ROS/NOS in skin carcinogenesis: the JB6 model is predictive. Mol Cell Biochem 234–235:185–193

    Article  PubMed  Google Scholar 

  5. Dinkova-Kostova AT, Fahey JW, Wade KL, Jenkins SN, Shapiro TA, Fuchs EJ, Kerns ML, Talalay P (2007) Induction of the phase 2 response in mouse and human skin by sulforaphane-containing broccoli sprout extracts. Cancer Epidemiol Biomarkers Prev 16:847–851

    Article  PubMed  CAS  Google Scholar 

  6. Hiratsuka A, Saito H, Hirose K, Watabe T (1999) Marked expression of glutathione S-transferase A 4-4 detoxifying 4-hydroxy-2(E)-nonenal in the skin of rats irradiated by ultraviolet B-band light (UVB). Biochem Biophys Res Commun 260:740–746

    Article  PubMed  CAS  Google Scholar 

  7. Ho T, Wei Q, Sturgis EM (2007) Epidemiology of carcinogen metabolism genes and risk of squamous cell carcinoma of the head and neck. Head Neck 29:682–699

    Article  PubMed  Google Scholar 

  8. Huang JX, Li FY, Xiao W, Song ZX, Qian RY, Chen P, Salminen E (2009) Expression of thymidylate synthase and glutathione-s-transferase pi in patients with esophageal squamous cell carcinoma. World J Gastroenterol 15:4316–4321

    Article  PubMed  CAS  Google Scholar 

  9. Itoh K, Ishii T, Wakabayashi N, Yamamoto M (1999) Regulatory mechanisms of cellular response to oxidative stress. Free Radic Res 31:319–324

    Article  PubMed  CAS  Google Scholar 

  10. Kambayashi H, Yamashita M, Odake Y, Takada K, Funasaka Y, Ichihashi M (2001) Epidermal changes caused by chronic low-dose UV irradiation induce wrinkle formation in hairless mouse. J Dermatol Sci 27(Suppl 1):S19–S25

    Article  PubMed  Google Scholar 

  11. Kobayashi A, Ohta T, Yamamoto M (2004) Unique function of the Nrf2-Keap1 pathway in the inducible expression of antioxidant and detoxifying enzymes. Methods Enzymol 378:273–286

    Article  PubMed  CAS  Google Scholar 

  12. Lee DS, Quan G, Choi JY, Kim SY, Lee SC (2005) Chronic ultraviolet radiation modulates epidermal differentiation as it up-regulates transglutaminase 1 and its substrates. Photodermatol Photoimmunol Photomed 21:45–52

    Article  PubMed  CAS  Google Scholar 

  13. Long DJ 2nd, Waikel RL, Wang XJ, Perlaky L, Roop DR, Jaiswal AK (2000) NAD(P)H:quinone oxidoreductase 1 deficiency increases susceptibility to benzo(a)pyrene-induced mouse skin carcinogenesis. Cancer Res 60:5913–5915

    PubMed  CAS  Google Scholar 

  14. Marrot L, Jones C, Perez P, Meunier JR (2008) The significance of Nrf2 pathway in (photo)-oxidative stress response in melanocytes and keratinocytes of the human epidermis. Pigment Cell Melanoma Res 21:79–88

    Article  PubMed  CAS  Google Scholar 

  15. Muramatsu S, Suga Y, Mizuno Y, Hasegawa T, Matsuba S, Hashimoto Y, Volkl A, Seitz J, Ogawa H (2005) Differentiation-specific localization of catalase and hydrogen peroxide, and their alterations in rat skin exposed to ultraviolet B rays. J Dermatol Sci 37:151–158

    Article  PubMed  CAS  Google Scholar 

  16. Myasoedova KN (2008) New findings in studies of cytochromes P450. Biochemistry (Mosc) 73:965–969

    Article  CAS  Google Scholar 

  17. Nishimura H, Yasui H, Sakurai H (2006) Generation and distribution of reactive oxygen species in the skin of hairless mice under UVA: studies on in vivo chemiluminescent detection and tape stripping methods. Exp Dermatol 15:891–899

    Article  PubMed  CAS  Google Scholar 

  18. Numata I, Okuyama R, Memezawa A, Ito Y, Takeda K, Furuyama K, Shibahara S, Aiba S (2009) Functional expression of heme oxygenase-1 in human differentiated epidermis and its regulation by cytokines. J Invest Dermatol 129:2594–2603

    Article  PubMed  CAS  Google Scholar 

  19. Piao MS, Choi JY, Lee DH, Yun SJ, Lee JB, Lee SC (2011) Differentiation-dependent expression of NADP(H):quinone oxidoreductase-1 via NF-E2 related factor-2 activation in human epidermal keratinocytes. J Dermatol Sci 62:147–153

    Article  PubMed  CAS  Google Scholar 

  20. Reiners JJ Jr, Thai G, Pavone A, Rupp T, Kodari E (1990) Modulation of catalase activities in murine epidermal cells as a function of differentiation and exposure to 12-O-tetradecanoylphorbol-13-acetate. Carcinogenesis 11:957–963

    Article  PubMed  CAS  Google Scholar 

  21. Sasaki H, Itoh T, Akamatsu H, Okamoto H, Horio T (2005) Effects of calcium concentration on the SOD activity and UVB-induced cytotoxicity in cultured human keratinocytes. Photodermatol Photoimmunol Photomed 21:9–14

    Article  PubMed  CAS  Google Scholar 

  22. Shih RH, Lee IT, Hsieh HL, Kou YR, Yang CM (2010) Cigarette smoke extract induces HO-1 expression in mouse cerebral vascular endothelial cells: involvement of c-Src/NADPH oxidase/PDGFR/JAK2/STAT3 pathway. J Cell Physiol 225:741–750

    Article  PubMed  CAS  Google Scholar 

  23. Shimizu K, Toriyama F, Yoshida H (1995) The expression of placental-type glutathione S-transferase (GST-pi) in human cutaneous squamous cell carcinoma and normal human skin. Virchows Arch 425:589–592

    Article  PubMed  CAS  Google Scholar 

  24. Strange RC, Spiteri MA, Ramachandran S, Fryer AA (2001) Glutathione-S-transferase family of enzymes. Mutat Res 482:21–2612

    Article  PubMed  CAS  Google Scholar 

  25. Surh YJ, Kundu JK, Na HK, Lee JS (2005) Redox-sensitive transcriptional factors as prime targets for chemoprevention with anti-inflammatory and antioxidative phytochemicals. J Nutr 135:2993S–3001S

    PubMed  CAS  Google Scholar 

  26. Tsuji MH, Yanagawa T, Iwasa S, Tabuchi K, Onizawa K, Bannai S, Toyooka H, Yoshida H (1999) Heme oxygenase-1 expression in oral squamous cell carcinoma as involved in lymph node metastasis. Cancer Lett 138:53–59

    Article  PubMed  CAS  Google Scholar 

  27. Tyrrell RM (2004) Solar ultraviolet A radiation: an oxidizing skin carcinogen that activates heme oxygenase-1. Antioxid Redox Signal 6:835–840

    PubMed  CAS  Google Scholar 

  28. Valacchi G, van der Vliet A, Schock BC, Okamoto T, Obermuller-Jevic U, Cross CE, Packer L (2002) Ozone exposure activates oxidative stress responses in murine skin. Toxicology 179:163–170

    Article  PubMed  CAS  Google Scholar 

  29. Yuspa SH, Hennings H, Tucker RW, Jaken S, Kilkenny AE, Roop DR (1988) Signal transduction for proliferation and differentiation in keratinocytes. Ann N Y Acad Sci 548:191–196

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by the High Value-Added Food Technology Development Program (109156-3), Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea.

Conflict of interest

The authors state no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Dermatology, Research Center for Photomedicine, Chonnam National University Medical School, 8 Hak-dong, Gwangju, 501-757, Korea

    Mei Shan Piao, Jae-Jeong Park, Jee-Young Choi, Dong-Hoon Lee, Sook Jung Yun, Jee-Bum Lee & Seung-Chul Lee

Authors
  1. Mei Shan Piao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jae-Jeong Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jee-Young Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dong-Hoon Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sook Jung Yun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jee-Bum Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Seung-Chul Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Seung-Chul Lee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Piao, M.S., Park, JJ., Choi, JY. et al. Nrf2-dependent and Nrf2-independent induction of phase 2 detoxifying and antioxidant enzymes during keratinocyte differentiation. Arch Dermatol Res 304, 387–395 (2012). https://doi.org/10.1007/s00403-012-1215-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00403-012-1215-7

Keywords

Search

Navigation