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Sci. STKE, 4 October 2005
Vol. 2005, Issue 304, p. pe48
[DOI: 10.1126/stke.3042005pe48]
PERSPECTIVES
Intracellular Glucocorticoid Signaling: A Formerly Simple System Turns Stochastic
George P. Chrousos1,2* and
Tomoshige Kino2
1Department of Pediatrics, University of Athens, Athens 115 27, Greece. 2Pediatric Endocrinology Section, Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
Abstract:
Glucocorticoids contribute fundamentally to the maintenance of basal and stress-related homeostasis in all higher organisms. The major roles of these steroids in physiology are amply matched by their remarkable contributions to pathology. Glucocorticoids influence about 20% of the expressed human genome, and their effects spare almost no organs or tissues. For many years we thought that the numerous actions of glucocorticoids were mediated by a single receptor molecule: the classic glucocorticoid receptor (GR) isoform α, a complex, multifunctional domain protein, operating as a ligand-dependent transcription factor. The GR gene, however, encodes two 3' splicing variants, GRα and GRβ, from alternative use of two distinct terminal exons (9α and 9β), and each variant mRNA is translated from at least eight initiation sites into multiple GRα and possibly GRβ isoforms, amounting to a minimum of 16 GR monomers and 256 different homo- or heterodimers. The translational GRα isoforms may be produced variably in target tissues, have varying intrinsic transcriptional activities, and influence different complements of glucocorticoid-responsive genes. It is likely that expression and functional differences might also be present between the putative GRβ translational isoforms. The presence of multiple GR monomers and dimers in different quantities with quantitatively and qualitatively different transcriptional activities suggests that the glucocorticoid signaling system is highly stochastic.
Entrainment of peripheral clock genes by cortisol.
P. D. Mavroudis, J. D. Scheff, S. E. Calvano, S. F. Lowry, and I. P. Androulakis (2012)
Physiol Genomics
44, 607-621
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Tumor Necrosis Factor Inhibits Glucocorticoid Receptor Function in Mice: A STRONG SIGNAL TOWARD LETHAL SHOCK.
T. Van Bogaert, S. Vandevyver, L. Dejager, F. Van Hauwermeiren, I. Pinheiro, I. Petta, D. Engblom, A. Kleyman, G. Schutz, J. Tuckermann, et al. (2011)
J. Biol. Chem.
286, 26555-26567
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Glucocorticoid Receptor {alpha} Isoform-Selective Regulation of Antiapoptotic Genes in Osteosarcoma Cells: A New Mechanism for Glucocorticoid Resistance.
K. L. Gross, R. H. Oakley, A. B. Scoltock, C. M. Jewell, and J. A. Cidlowski (2011)
Mol. Endocrinol.
25, 1087-1099
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Cellular Processing of the Glucocorticoid Receptor Gene and Protein: New Mechanisms for Generating Tissue-specific Actions of Glucocorticoids.
Noncoding RNA Gas5 Is a Growth Arrest- and Starvation-Associated Repressor of the Glucocorticoid Receptor.
T. Kino, D. E. Hurt, T. Ichijo, N. Nader, and G. P. Chrousos (2010)
Science Signaling
3, ra8
|Abstract »|Full Text »|PDF »
Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications.
