Tissue Glucocorticoid Sensitivity: Beyond Stochastic Regulation on the Diverse Actions of Glucocorticoids

Abstract

Glucocorticoids have a broad array of life-sustaining functions, such as for the maintenance of the basal- and stress-related organ homeostasis. They are also frequently used as therapeutic compounds for many pathologic conditions. Thus, changes of tissue sensitivity to glucocorticoids play important roles in the physiologic conditions and are associated with and influence the course of numerous pathologic states. Changes in tissue glucocorticoid sensitivity may present on either side of an optimal range, respectively as glucocorticoid resistance or hypersensitivity, and may be generalized or tissue-specific. Recent insights into the mechanisms of the glucocorticoid receptor (GR) action indicated that the glucocorticoid signaling system is highly stochastic. Indeed, numerous factors contribute to the hormonal action at each step of the GR signaling cascade, such as ligand availability, receptor isoform expression, intracellular circulation, promoter association, attraction of cofactors, and finally clearance of the receptor from the target genes. Importantly, these regulatory mechanisms appear to be functional in tissue-, gene- and cellular biologic state-specific fashions. As an example of such phase-specific factors, we discussed influence of the cyclin-dependent kinase 5 to the GR transcriptional activity, which specifically functions in the central nervous system and may thus play an important role in the regulation of glucocorticoid action in this organ.

Tissue glucocorticoid sensitivity - glucocorticoid receptor - cyclin-dependent kinase 5

References

• 1 Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation.  N Engl J Med. 1995;  332 1351-1362
• 2 Orth DN, Kovacs WJ, DeBold CR. The adrenal cortex. In: Wilson JD, Foster DW, Kronenberg HM, Larsen R (eds). Textbook of Endocrinology. 9th ed. Philadelphia: W. B. Saunders Co. 1998: 517-664
• 3 Chrousos GP. Glucocorticoid therapy. In: Felig P, Frohman LA (eds). Endocrinology & Metabolism. 4th ed. New York: McGraw-Hill 2001: 609-632
• 4 Kino T, Chrousos GP. Glucocorticoid and mineralocorticoid receptors and associated diseases.  Essays Biochem. 2004;  40 137-155
• 5 Kino T, Chrousos GP. Glucocorticoid effects on gene expression. In: Steckler T, Kalin NH, Reul JMHM (eds). Handbook of stress and the brain. Amsterdam, The Netherlands: Elsevier B. V. 2005: 295-311
• 6 Galon J, Franchimont D, Hiroi N, Frey G, Boettner A, Ehrhart-Bornstein M, O’Shea JJ, Chrousos GP, Bornstein SR. Gene profiling reveals unknown enhancing and suppressive actions of glucocorticoids on immune cells.  FASEB J. 2002;  16 61-71
• 7 Bamberger CM, Bamberger AM, de Castro M, Chrousos GP. Glucocorticoid receptor beta, a potential endogenous inhibitor of glucocorticoid action in humans.  J Clin Invest. 1995;  95 2435-2441
• 8 Lu NZ, Cidlowski JA. Translational regulatory mechanisms generate N-terminal glucocorticoid receptor isoforms with unique transcriptional target genes.  Mol Cell. 2005;  18 331-342
• 9 Hollenberg SM, Weinberger C, Ong ES, Cerelli G, Oro A, Lebo R, Thompson EB, Rosenfeld MG, Evans RM. Primary structure and expression of a functional human glucocorticoid receptor cDNA.  Nature. 1985;  318 635-641
• 10 Chrousos GP, Kino T. Intracellular glucocorticoid signaling: a formerly simple system turns stochastic.  Sci STKE. 2005;  2005 pe48
• 11 Kino T, De Martino MU, Charmandari E, Mirani M, Chrousos GP. Tissue glucocorticoid resistance/hypersensitivity syndromes.  J Steroid Biochem Mol Biol. 2003;  85 457-467
• 12 De Martino MU, Bhattachryya N, Alesci S, Ichijo T, Chrousos GP, Kino T. The glucocorticoid receptor and the orphan nuclear receptor chicken ovalbumin upstream promoter-transcription factor II interact with and mutually affect each other's transcriptional activities: implications for intermediary metabolism.  Mol Endocrinol. 2004;  18 820-833
• 13 Ichijo T, Voutetakis A, Cotrim AP, Bhattachryya N, Fujii M, Chrousos GP, Kino T. The Smad6-histone deacetylase 3 complex silences the transcriptional activity of the glucocorticoid receptor: potential clinical implications.  J Biol Chem. 2005;  280 42067-42077
• 14 Rosenfeld MG, Lunyak VV, Glass CK. Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response.  Genes Dev. 2006;  20 1405-1428
• 15 Huang EY, Zhang J, Miska EA, Guenther MG, Kouzarides T, Lazar MA. Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway.  Genes Dev. 2000;  14 45-54
• 16 Wang Q, Blackford Jr. JA, Song LN, Huang Y, Cho S, Simons Jr. SS. Equilibrium interactions of corepressors and coactivators with agonist and antagonist complexes of glucocorticoid receptors.  Mol Endocrinol. 2004;  18 1376-1395
• 17 Schulz M, Eggert M, Baniahmad A, Dostert A, Heinzel T, Renkawitz R. RU486-induced glucocorticoid receptor agonism is controlled by the receptor N terminus and by corepressor binding.  J Biol Chem. 2002;  277 26238-26243
• 18 Kino T, Chrousos GP. Tissue-specific glucocorticoid resistance-hypersensitivity syndromes: multifactorial states of clinical importance.  J Allergy Clin Immunol. 2002;  109 609-613
• 19 Meduri GU, Yates CR. Systemic inflammation-associated glucocorticoid resistance and outcome of ARDS.  Ann N Y Acad Sci. 2004;  1024 24-53
• 20 Chrousos GP. The role of stress and the hypothalamic-pituitary-adrenal axis in the pathogenesis of the metabolic syndrome: neuro-endocrine and target tissue-related causes.  Int J Obes Relat Metab Disord. 2000;  24 ((Suppl 2)) S50-S55
• 21 Kino T, Gragerov A, Kopp JB, Stauber RH, Pavlakis GN, Chrousos GP. The HIV-1 virion-associated protein vpr is a coactivator of the human glucocorticoid receptor.  J Exp Med. 1999;  189 51-62
• 22 Kino T, Mirani M, Alesci S, Chrousos GP. AIDS-related lipodystrophy/insulin resistance syndrome.  Horm Metab Res. 2003;  35 129-136
• 23 Webster JI, Carlstedt-Duke J. Involvement of multidrug resistance proteins (MDR) in the modulation of glucocorticoid response.  J Steroid Biochem Mol Biol. 2002;  82 277-288
• 24 Kinyamu HK, Chen J, Archer TK. Linking the ubiquitin-proteasome pathway to chromatin remodeling/modification by nuclear receptors.  J Mol Endocrinol. 2005;  34 281-297
• 25 Ismaili N, Garabedian MJ. Modulation of glucocorticoid receptor function via phosphorylation.  Ann N Y Acad Sci. 2004;  1024 86-101
• 26 Krstic MD, Rogatsky I, Yamamoto KR, Garabedian MJ. Mitogen-activated and cyclin-dependent protein kinases selectively and differentially modulate transcriptional enhancement by the glucocorticoid receptor.  Mol Cell Biol. 1997;  17 3947-3954
• 27 Wang Z, Frederick J, Garabedian MJ. Deciphering the phosphorylation “code” of the glucocorticoid receptor in vivo.  J Biol Chem. 2002;  277 26573-26580
• 28 Miller AL, Webb MS, Copik AJ, Wang Y, Johnson BH, Kumar R, Thompson EB. p38 Mitogen-activated protein kinase (MAPK) is a key mediator in glucocorticoid-induced apoptosis of lymphoid cells: correlation between p38 MAPK activation and site-specific phosphorylation of the human glucocorticoid receptor at serine 211.  Mol Endocrinol. 2005;  19 1569-1583
• 29 Itoh M, Adachi M, Yasui H, Takekawa M, Tanaka H, Imai K. Nuclear export of glucocorticoid receptor is enhanced by c-Jun N-terminal kinase-mediated phosphorylation.  Mol Endocrinol. 2002;  16 2382-2392
• 30 Ismaili N, Blind R, Garabedian MJ. Stabilization of the unliganded glucocorticoid receptor by TSG101.  J Biol Chem. 2005;  280 11120-11126
• 31 Kesavapany S, Li BS, Pant HC. Cyclin-dependent kinase 5 in neurofilament function and regulation.  Neurosignals. 2003;  12 252-264
• 32 Kino T, Ichijo T, Amin ND, Kesavapany S, Wang YH, Kim N, Rao S, Player A, Zeng YL, Garabedian MJ, Kawasaki A, Pant HC, Chrousos GP. Cyclin-dependent kinase 5 differentially regulates the transcriptional activity of the glucocorticoid receptor through phosphorylating: clinical implications for the nervous system response to glucocorticoids and stress.  Mol Endocrinol . . 2007;  , in press
• 33 Ohshima T, Ward JM, Huh CG, Longenecker G, Veeranna , Pant HC, Brady RO, Martin LJ, Kulkarni AB. Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death.  Proc Natl Acad Sci USA. 1996;  93 11173-11178
• 34 Dhavan R, Tsai LH. A decade of CDK5.  Nat Rev Mol Cell Biol. 2001;  2 749-759
• 35 Tsai LH, Delalle I, Caviness Jr. VS, Chae T, Harlow E. p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5.  Nature. 1994;  371 419-423
• 36 Tang D, Wang JH. Cyclin-dependent kinase 5 (Cdk5) and neuron-specific Cdk5 activators.  Prog Cell Cycle Res. 1996;  2 205-216
• 37 Lau LF, Seymour PA, Sanner MA, Schachter JB. Cdk5 as a drug target for the treatment of Alzheimer's disease.  J Mol Neurosci. 2002;  19 267-273
• 38 Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH. Neurotoxicity induces cleavage of p35 to p25 by calpain.  Nature. 2000;  405 360-364
• 39 Kusakawa G, Saito T, Onuki R, Ishiguro K, Kishimoto T, Hisanaga S. Calpain-dependent proteolytic cleavage of the p35 cyclin-dependent kinase 5 activator to p25.  J Biol Chem. 2000;  275 17166-17172
• 40 Sun Z, Pan J, Hope WX, Cohen SN, Balk SP. Tumor susceptibility gene 101 protein represses androgen receptor transactivation and interacts with p300.  Cancer. 1999;  86 689-696
• 41 Holsboer F, Barden N. Antidepressants and hypothalamic-pituitary-adrenocortical regulation.  Endocr Rev. 1996;  17 187-205
• 42 Ahlijanian MK, Barrezueta NX, Williams RD, Jakowski A, Kowsz KP, McCarthy S, Coskran T, Carlo A, Seymour PA, Burkhardt JE, Nelson RB, McNeish JD. Hyperphosphorylated tau and neurofilament and cytoskeletal disruptions in mice overexpressing human p25, an activator of cdk5.  Proc Natl Acad Sci USA. 2000;  97 2910-2915
• 43 Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration.  Nature. 1999;  402 615-622

Correspondence