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Mol. Cell. Biol. 20 (12): 4328-4339

Copyright © 2000 by the American Society for Microbiology. All rights reserved.

Molecular and Cellular Biology, June 2000, p. 4328-4339, Vol. 20, No. 12
Copyright © 2000, American Society for Microbiology. All rights reserved.

Novel Mechanism of Steroid Action in Skin through Glucocorticoid Receptor Monomers

Nadezda Radoja,1,2 Mayumi Komine,1,3 Sang H. Jho,1 Miroslav Blumenberg,1,4 and Marjana Tomic-Canic1,2,*

The Ronald O. Perelman Department of Dermatology1 and Biochemistry,4 New York University School of Medicine, New York, New York, 10016; Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo, Japan3; and Institute "Vinca," Belgrade, Yugoslavia2

Received 16 August 1999/Returned for modification 1 October 1999/Accepted 20 March 2000

Glucocorticoids (GCs), important regulators of epidermal growth, differentiation, and homeostasis, are used extensively in the treatment of skin diseases. Using keratin gene expression as a paradigm of epidermal physiology and pathology, we have developed a model system to study the molecular mechanism of GCs action in skin. Here we describe a novel mechanism of suppression of transcription by the glucocorticoid receptor (GR) that represents an example of customizing a device for transcriptional regulation to target a specific group of genes within the target tissue, in our case, epidermis. We have shown that GCs repress the expression of the basal-cell-specific keratins K5 and K14 and disease-associated keratins K6, K16, and K17 but not the differentiation-specific keratins K3 and K10 or the simple epithelium-specific keratins K8, K18, and K19. We have identified the negative recognition elements (nGREs) in all five regulated keratin gene promoters. Detailed footprinting revealed that the function of nGREs is to instruct the GR to bind as four monomers. Furthermore, using cotransfection and antisense technology we have found that, unlike SRC-1 and GRIP-1, which are not involved in the GR complex that suppresses keratin genes, histone acetyltransferase and CBP are. In addition, we have found that GR, independently from GREs, blocks the induction of keratin gene expression by AP1. We conclude that GR suppresses keratin gene expression through two independent mechanisms: directly, through interactions of keratin nGREs with four GR monomers, as well as indirectly, by blocking the AP1 induction of keratin gene expression.

* Corresponding author. Mailing address: The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, 550 First Ave., TH 361, New York, NY 10016. Phone: (212) 263-5931. Fax: (212) 263-8752. E-mail: tomicm01{at}

Molecular and Cellular Biology, June 2000, p. 4328-4339, Vol. 20, No. 12
Copyright © 2000, American Society for Microbiology. All rights reserved.

Cortisol Synthesis in Epidermis Is Induced by IL-1 and Tissue Injury.
S. Vukelic, O. Stojadinovic, I. Pastar, M. Rabach, A. Krzyzanowska, E. Lebrun, S. C. Davis, S. Resnik, H. Brem, and M. Tomic-Canic (2011)
J. Biol. Chem. 286, 10265-10275
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Abrogation of Glucocorticoid Receptor Dimerization Correlates with Dissociated Glucocorticoid Behavior of Compound A.
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Farnesyl Pyrophosphate Inhibits Epithelialization and Wound Healing through the Glucocorticoid Receptor.
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J. Biol. Chem. 285, 1980-1988
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Glucocorticoid repression of human with-no-lysine (K) kinase-4 gene expression is mediated by the negative response elements in the promoter.
C. Li, Y. Li, Y. Li, H. Liu, Z. Sun, J. Lu, and Y. Zhao (2008)
J. Mol. Endocrinol. 40, 3-12
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O. Stojadinovic, B. Lee, C. Vouthounis, S. Vukelic, I. Pastar, M. Blumenberg, H. Brem, and M. Tomic-Canic (2007)
J. Biol. Chem. 282, 4021-4034
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Thyroid Hormones and Gamma Interferon Specifically Increase K15 Keratin Gene Transcription.
N. Radoja, O. Stojadinovic, A. Waseem, M. Tomic-Canic, V. Milisavljevic, S. Teebor, and M. Blumenberg (2004)
Mol. Cell. Biol. 24, 3168-3179
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Pemphigus Vulgaris IgG and Methylprednisolone Exhibit Reciprocal Effects on Keratinocytes.
V. T. Nguyen, J. Arredondo, A. I. Chernyavsky, Y. Kitajima, M. Pittelkow, and S. A. Grando (2004)
J. Biol. Chem. 279, 2135-2146
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Dissection of a Complex Enhancer Element: Maintenance of Keratinocyte Specificity but Loss of Differentiation Specificity.
C. K. Kaufman, S. Sinha, D. Bolotin, J. Fan, and E. Fuchs (2002)
Mol. Cell. Biol. 22, 4293-4308
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Negative Response Elements in Keratin Genes Mediate Transcriptional Repression and the Cross-talk among Nuclear Receptors.
S. H. Jho, N. Radoja, M. J. Im, and M. Tomic-Canic (2001)
J. Biol. Chem. 276, 45914-45920
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Heterodimerization of Mineralocorticoid and Glucocorticoid Receptors at a Novel Negative Response Element of the 5-HT1A Receptor Gene.
X.-M. Ou, J. M. Storring, N. Kushwaha, and P. R. Albert (2001)
J. Biol. Chem. 276, 14299-14307
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The POU Domain Factor Skin-1a Represses the Keratin 14 Promoter Independent of DNA Binding. A POSSIBLE ROLE FOR INTERACTIONS BETWEEN Skn-1a AND CREB-BINDING PROTEIN/p300.
T. M. Sugihara, E. I. Kudryavtseva, V. Kumar, J. J. Horridge, and B. Andersen (2001)
J. Biol. Chem. 276, 33036-33044
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Chromatin Remodeling by the Thyroid Hormone Receptor in Regulation of the Thyroid-stimulating Hormone alpha -Subunit Promoter.
T. N. Collingwood, F. D. Urnov, V. K. K. Chatterjee, and A. P. Wolffe (2001)
J. Biol. Chem. 276, 34227-34234
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