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
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fsj.onc.1210108/MediaObjects/41388_2007_Article_BF1210108_Fig1_HTML.jpg)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fsj.onc.1210108/MediaObjects/41388_2007_Article_BF1210108_Fig2_HTML.jpg)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fsj.onc.1210108/MediaObjects/41388_2007_Article_BF1210108_Fig3_HTML.jpg)
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.
Beato M, Herrlich P, Schultz G . (1995). Steroid hormone receptors: many actors in search of a plot. Cell 83: 851–857.
Bickenbach JR, Mackenzie IC . (1984). Identification and localization of label-retaining cells in hamster epithelia. J Invest Dermatol 82: 618–622.
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.
Blanpain C, Fuchs E . (2006). Epidermal Stem Cells of the Skin. Annu Rev Cell Dev Biol 22: 339–373.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Fuchs E, Merrill BJ, Jamora C, DasGupta R . (2001). At the roots of a never-ending cycle. Dev Cell 1: 13–25.
Herold MJ, McPherson KG, Reichardt HM . (2006). Glucocorticoids in T cell apoptosis and function. Cell Mol Life Sci 63: 60–72.
Hubler TR, Scammell JG . (2004). Intronic hormone response elements mediate regulation of FKBP5 by progestins and glucocorticoids. Cell Stress Chaperones 9: 243–252.
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.
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.
Lavker RM, Sun TT . (2000). Epidermal stem cells: properties, markers, and location. Proc Natl Acad Sci USA 97: 13473–13475.
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.
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.
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.
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.
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.
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.
Morris RJ . (2000). Keratinocyte stem cells: targets for cutaneous carcinogens. J Clin Invest 106: 3–8.
Necela BM, Cidlowski JA . (2004). Mechanisms of glucocorticoid receptor action in noninflammatory and inflammatory cells. Proc Am Thorac Soc 1: 239–246.
Owens DM, Watt FM . (2003). Contribution of stem cells and differentiated cells to epidermal tumours. Nat Rev Cancer 3: 444–451.
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.
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.
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.
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.
Smith E, Sigvardsson M . (2004). The roles of transcription factors in B lymphocyte commitment, development, and transformation. J Leukoc Biol 75: 973–981.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
Rights 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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1210108
Keywords
This article is cited by
-
Simulated microgravity significantly altered metabolism in epidermal stem cells
In Vitro Cellular & Developmental Biology - Animal (2020)
-
Enrichment of putative human epidermal stem cells based on cell size and collagen type IV adhesiveness
Cell Research (2008)
-
Epithelial Cells in the Hair Follicle Bulge do not Contribute to Epidermal Regeneration after Glucocorticoid-Induced Cutaneous Atrophy
Journal of Investigative Dermatology (2007)