Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The tumor suppressor effect of the glucocorticoid receptor in skin is mediated via its effect on follicular epithelial stem cells

Oncogene volume 26, pages 3060–3068 (2007)Cite this article

Abstract

Glucocorticoids are potent inhibitors of mouse skin tumorigenesis. The glucocorticoid control of cellular functions is mediated via the glucocorticoid receptor (GR), a well-known transcription factor. Recently, we generated transgenic mice overexpressing GR under control of the keratin5 (K5) promoter, and showed that K5.GR animals are resistant to skin carcinogenesis. Follicular epithelial stem cells (SCs), located in the bulge region of the hair follicle, are believed to be one of the target cells for skin carcinogenesis. We found that the number of putative hair follicle SC detected as label-retaining cells was significantly less in the K5.GR transgenics compared to wild type (w.t.) littermates. We also showed that GR overexpression led to a reduction in the clonogenicity of the follicular epithelial SCs. We evaluated the global effect of GR on gene expression in a population of follicular SC-enriched bulge keratinocytes isolated by fluorescence activated cell sorting. We found that GR affected the expression of numerous bulge SC ‘signature’ genes, genes involved in the maintenance of SC and progenitor cells of non-epidermal origin and proapoptotic genes. Our findings underscore the important role of GR signaling in the homeostasis of follicular epithelial SCs, and suggest that the reduction in their number may underlie the tumor suppressor effect of GR in the skin.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

Abbreviations

BrdU:

5-bromo-2-deoxyuridine

GR:

glucocorticoid receptor

GRE:

glucocorticoid-response element

HSP:

heat shock protein

K5:

keratin5

LRCs:

label-retaining cells

Q-PCR:

quantitative PCR

SC:

stem cells

SCC:

squamous cell carcinoma

s.c.:

subcutaneous

TA cells:

transient amplifying cells

w.t.:

wild type

References

  • Bauer A, Tronche F, Wessely O, Kellendonk C, Reichardt HM, Steinlein P et al. (1999). The glucocorticoid receptor is required for stress erythropoiesis. Genes Dev 13: 2996–3002.

    Article  CAS  Google Scholar 

  • Beato M, Herrlich P, Schultz G . (1995). Steroid hormone receptors: many actors in search of a plot. Cell 83: 851–857.

    Article  CAS  Google Scholar 

  • Bickenbach JR, Mackenzie IC . (1984). Identification and localization of label-retaining cells in hamster epithelia. J Invest Dermatol 82: 618–622.

    Article  CAS  Google Scholar 

  • Blanpain C, Lowry WE, Geoghegan A, Polak L, Fuchs E . (2004). Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118: 635–648.

    Article  CAS  Google Scholar 

  • Blanpain C, Fuchs E . (2006). Epidermal Stem Cells of the Skin. Annu Rev Cell Dev Biol 22: 339–373.

    Article  CAS  Google Scholar 

  • Budunova IV, Kang H, Carbajal S, Viaje A, Slaga TJ . (1997). Altered glucocorticoid receptor expression and function during mouse skin carcinogenesis. Mol Carcinogen 18: 177–185.

    Article  CAS  Google Scholar 

  • Budunova IV, Kowalczyk D, Perez P, Yao YJ, Jorcano JL, Slaga TJ . (2003). Glucocorticoid receptor functions as a potent suppressor of mouse skin carcinogenesis. Oncogene 22: 3279–3287.

    Article  CAS  Google Scholar 

  • Costoya JA, Hobbs RM, Barna M, Cattoretti G, Manova K, Sukhwani M et al. (2004). Essential role of Plzf in maintenance of spermatogonial stem cells. Nat Genet 36: 653–659.

    Article  CAS  Google Scholar 

  • Cotsarelis G, Sun TT, Lavker RM . (1990). Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell 61: 1329–1337.

    Article  CAS  Google Scholar 

  • Daniel PT, Wieder T, Sturm I, Schulze-Osthoff K . (2001). The kiss of death: promises and failures of death receptors and ligands in cancer therapy. Leukemia 15: 1022–1032.

    Article  CAS  Google Scholar 

  • Davies TH, Ning YM, Sanchez ER . (2002). A new first step in activation of steroid receptors: hormone-induced switching of FKBP51 and FKBP52 immunophilins. J Biol Chem 277: 4597–4600.

    Article  CAS  Google Scholar 

  • Davies TH, Ning YM, Sanchez ER . (2005). Differential control of glucocorticoid receptor hormone-binding function by tetratricopeptide repeat (TPR) proteins and the immunosuppressive ligand FK506. Biochemistry 44: 2030–2038.

    Article  CAS  Google Scholar 

  • De Bosscher K, Vanden Berghe W, Haegeman G . (2003). The interplay between the glucocorticoid receptor and nuclear factor-kappaB or activator protein-1: molecular mechanisms for gene repression. Endocr Rev 24: 488–522.

    Article  CAS  Google Scholar 

  • Derfoul A, Perkins GL, Hall DJ, Tuan RS . (2006). Glucocorticoids promote chondrogenic differentiation of adult human mesenchymal stem cells by enhancing expression of cartilage extracellular matrix genes. Stem Cells 24: 1487–1495.

    Article  CAS  Google Scholar 

  • Dumitriu B, Patrick MR, Petschek JP, Cherukuri S, Klingmuller U, Fox PL et al. (2006). Sox6 cell-autonomously stimulates erythroid cell survival, proliferation, and terminal maturation and is thereby an important enhancer of definitive erythropoiesis during mouse development. Blood 108: 1198–1207.

    Article  CAS  Google Scholar 

  • Fuchs E, Merrill BJ, Jamora C, DasGupta R . (2001). At the roots of a never-ending cycle. Dev Cell 1: 13–25.

    Article  CAS  Google Scholar 

  • Herold MJ, McPherson KG, Reichardt HM . (2006). Glucocorticoids in T cell apoptosis and function. Cell Mol Life Sci 63: 60–72.

    Article  CAS  Google Scholar 

  • Hubler TR, Scammell JG . (2004). Intronic hormone response elements mediate regulation of FKBP5 by progestins and glucocorticoids. Cell Stress Chaperones 9: 243–252.

    Article  CAS  Google Scholar 

  • Ito C, Sato H, Ando K, Watanabe S, Yoshiba F, Kishi K et al. (2003). Serum stem cell growth factor for monitoring hematopoietic recovery following stem cell transplantation. Bone Marrow Transplant 32: 391–398.

    Article  CAS  Google Scholar 

  • Lavker RM, Sun TT, Oshima H, Barrandon Y, Akiyama M, Ferraris C et al. (2003). Hair follicle stem cells. J Investig Dermatol Symp Proc 8: 28–38.

    Article  Google Scholar 

  • Lavker RM, Sun TT . (2000). Epidermal stem cells: properties, markers, and location. Proc Natl Acad Sci USA 97: 13473–13475.

    Article  CAS  Google Scholar 

  • Li BG, Hasselgren PO, Fang CH . (2005). Insulin-like growth factor-I inhibits dexamethasone-induced proteolysis in cultured L6 myotubes through PI3K/Akt/GSK-3beta and PI3K/Akt/mTOR-dependent mechanisms. Int J Biochem Cell Biol 37: 2207–2216.

    Article  CAS  Google Scholar 

  • Li G, Wang S, Gelehrter TD . (2003). Identification of glucocorticoid receptor domains involved in transrepression of transforming growth factor-beta action. J Biol Chem 278: 41779–41788.

    Article  CAS  Google Scholar 

  • Ligon KL, Kesari S, Kitada M, Sun T, Arnett HA, Alberta JA et al. (2006). Development of NG2 neural progenitor cells requires Olig gene function. Proc Natl Acad Sci USA 103: 7853–7858.

    Article  CAS  Google Scholar 

  • Lu J, Quearry B, Harada H . (2006). p38-MAP kinase activation followed by BIM induction is essential for glucocorticoid-induced apoptosis in lymphoblastic leukemia cells. FEBS Lett 580: 3539–3544.

    Article  CAS  Google Scholar 

  • Morris RJ, Fischer SM, Slaga TJ . (1985). Evidence that the centrally and peripherally located cells in the murine epidermal proliferative unit are two distinct cell populations. J Invest Dermatol 84: 277–281.

    Article  CAS  Google Scholar 

  • Morris RJ, Liu Y, Marles L, Yang Z, Trempus C, Li S et al. (2004). Capturing and profiling adult hair follicle stem cells. Nat Biotechnol 22: 411–417.

    Article  CAS  Google Scholar 

  • Morris RJ . (2000). Keratinocyte stem cells: targets for cutaneous carcinogens. J Clin Invest 106: 3–8.

    Article  CAS  Google Scholar 

  • Necela BM, Cidlowski JA . (2004). Mechanisms of glucocorticoid receptor action in noninflammatory and inflammatory cells. Proc Am Thorac Soc 1: 239–246.

    Article  CAS  Google Scholar 

  • Owens DM, Watt FM . (2003). Contribution of stem cells and differentiated cells to epidermal tumours. Nat Rev Cancer 3: 444–451.

    Article  CAS  Google Scholar 

  • Perez P, Page A, Bravo A, Del Rio M, Gimenez-Conti I, Budunova I et al. (2001). Altered skin development and impaired proliferative and inflammatory responses in transgenic mice overexpressing the glucocorticoid receptor. FASEB J 15: 2030–2032.

    Article  CAS  Google Scholar 

  • Pratt WB, Toft DO . (2003). Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med (Maywood) 228: 111–133.

    Article  CAS  Google Scholar 

  • Schwartz JA, Viaje A, Slaga TJ, Yuspa SH, Hennings H, Lihta U . (1977). Fluocinolone acetonide: a potent inhibitor of mouse skin tumor promotion and epidermal DNA synthesis. Chem-Biol Interaction 17: 331–347.

    Article  Google Scholar 

  • Schwarz-Romond T, Asbrand C, Bakkers J, Kuhl M, Schaeffer HJ, Huelsken J et al. (2002). The ankyrin repeat protein Diversin recruits Casein kinase Iepsilon to the beta-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling. Genes Dev 16: 2073–2084.

    Article  CAS  Google Scholar 

  • Smith E, Sigvardsson M . (2004). The roles of transcription factors in B lymphocyte commitment, development, and transformation. J Leukoc Biol 75: 973–981.

    Article  CAS  Google Scholar 

  • Su HP, Nakada-Tsukui K, Tosello-Trampont AC, Li Y, Bu G, Henson PM et al. (2002). Interaction of CED-6/GULP, an adapter protein involved in engulfment of apoptotic cells with CED-1 and CD91/low density lipoprotein receptor-related protein (LRP). J Biol Chem 277: 11772–11779.

    Article  CAS  Google Scholar 

  • Takayama S, Rogatsky I, Schwarcz LE, Darimont BD . (2006). The Glucocorticoid receptor represses cyclin D1 by targeting the Tcf-beta-catenin complex. J Biol Chem 281: 17856–17863.

    Article  CAS  Google Scholar 

  • Taylor G, Lehrer MS, Jensen PJ, Sun TT, Lavker RM . (2000). Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell 102: 451–461.

    Article  CAS  Google Scholar 

  • Trempus CS, Morris RJ, Bortner CD, Cotsarelis G, Faircloth RS, Reece JM et al. (2003). Enrichment for living murine keratinocytes from the hair follicle bulge with the cell surface marker CD34. J Invest Dermatol 120: 501–511.

    CAS  PubMed  Google Scholar 

  • Tumbar T, Guasch G, Greco V, Blanpain C, Lowry WE, Rendl M et al. (2004). Defining the epithelial stem cell niche in skin. Science 303: 359–363.

    Article  CAS  Google Scholar 

  • Verma AK, Garcia CT, Ashendel CL, Boutwell RK . (1983). Inhibition of 7-bromomethylbenz[a]anthracene-promoted mouse skin tumor formation by retinoic acid and dexamethasone. Cancer Res 43: 3045–3049.

    CAS  PubMed  Google Scholar 

  • Ward AC, Loeb DM, Soede-Bobok AA, Touw IP, Friedman AD . (2000). Regulation of granulopoiesis by transcription factors and cytokine signals. Leukemia 14: 973–990.

    Article  CAS  Google Scholar 

  • Yao R, Wang Y, Lemon WJ, Lubet RA, You M . (2004). Budesonide exerts its chemopreventive efficacy during mouse lung tumorigenesis by modulating gene expressions. Oncogene 23: 7746–7752.

    Article  CAS  Google Scholar 

  • Yemelyanov A, Gasparian A, Lindholm P, Dang L, Pierce JW, Kisseljov F et al. (2006). Effects of IKK inhibitor PS1145 on NF-kappaB function, proliferation, apoptosis and invasion activity in prostate carcinoma cells. Oncogene 25: 387–398.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr C Trempus (National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA) and Dr N Jafari (Microarray & Genotyping cores, Center for Genetic Medicine, Northwestern University, Chicago, IL, USA) for technical support. We are thankful to Dr D Smith (Mayo Clinic, Scottsdale, AZ, USA) for his generous gift of anti-Fkbp51 Ab.

Author information

Authors and Affiliations

  1. Department of Dermatology, Feinberg Medical School, Northwestern University, Chicago, IL, USA

    D Chebotaev, A Yemelyanov, R M Lavker & I Budunova

  2. Bioinformatics Core, Northwestern University, Chicago, IL, USA

    L Zhu

Authors
  1. D Chebotaev
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Yemelyanov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R M Lavker
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. I Budunova
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I Budunova.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chebotaev, D., Yemelyanov, A., Zhu, L. et al. The tumor suppressor effect of the glucocorticoid receptor in skin is mediated via its effect on follicular epithelial stem cells. Oncogene 26, 3060–3068 (2007). https://doi.org/10.1038/sj.onc.1210108

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210108

Keywords

This article is cited by

Search

Advanced search

Quick links