1932

Abstract

Glucocorticoid hormones (GC) regulate essential physiological functions including energy homeostasis, embryonic and postembryonic development, and the stress response. From the biomedical perspective, GC have garnered a tremendous amount of attention as highly potent anti-inflammatory and immunosuppressive medications indispensable in the clinic. GC signal through the GC receptor (GR), a ligand-dependent transcription factor whose structure, DNA binding, and the molecular partners that it employs to regulate transcription have been under intense investigation for decades. In particular, next-generation sequencing–based approaches have revolutionized the field by introducing a unified platform for a simultaneous genome-wide analysis of cellular activities at the level of RNA production, binding of transcription factors to DNA and RNA, and chromatin landscape and topology. Here we describe fundamental concepts of GC/GR function as established through traditional molecular and in vivo approaches and focus on the novel insights of GC biology that have emerged over the last 10 years from the rapidly expanding arsenal of system-wide genomic methodologies.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-021115-105323
2016-02-10
2024-04-18
Loading full text...

Full text loading...

/deliver/fulltext/physiol/78/1/annurev-physiol-021115-105323.html?itemId=/content/journals/10.1146/annurev-physiol-021115-105323&mimeType=html&fmt=ahah

Literature Cited

  1. Angelier F, Wingfield JC. 1.  2013. Importance of the glucocorticoid stress response in a changing world: theory, hypotheses and perspectives. Gen. Comp. Endocrinol. 190:118–28 [Google Scholar]
  2. Walker JJ, Spiga F, Waite E, Zhao Z, Kershaw Y. 2.  et al. 2012. The origin of glucocorticoid hormone oscillations. PLOS Biol. 10:e1001341 [Google Scholar]
  3. Landys MM, Ramenofsky M, Wingfield JC. 3.  2006. Actions of glucocorticoids at a seasonal baseline as compared to stress-related levels in the regulation of periodic life processes. Gen. Comp. Endocrinol. 148:132–49 [Google Scholar]
  4. Oakley RH, Cidlowski JA. 4.  2013. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J. Allergy Clin. Immunol. 132:1033–44 [Google Scholar]
  5. Romero LM, Dickens MJ, Cyr NE. 5.  2009. The Reactive Scope Model—a new model integrating homeostasis, allostasis, and stress. Horm. Behav. 55:375–89 [Google Scholar]
  6. Crespi EJ, Williams TD, Jessop TS, Delehanty B. 6.  2013. Life history and the ecology of stress: How do glucocorticoid hormones influence life-history variation in animals?. Funct. Ecol. 27:93–106 [Google Scholar]
  7. Simons SS Jr. 7.  2008. What goes on behind closed doors: physiological versus pharmacological steroid hormone actions. BioEssays 30:744–56 [Google Scholar]
  8. Vandevyver S, Dejager L, Libert C. 8.  2012. On the trail of the glucocorticoid receptor: into the nucleus and back. Traffic 13:364–74 [Google Scholar]
  9. Vandevyver S, Dejager L, Libert C. 9.  2014. Comprehensive overview of the structure and regulation of the glucocorticoid receptor. Endocr. Rev. 35:671–93 [Google Scholar]
  10. Gomez-Sanchez E, Gomez-Sanchez CE. 10.  2014. The multifaceted mineralocorticoid receptor. Compr. Physiol. 4:965–94 [Google Scholar]
  11. Thornton JW. 11.  2001. Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. PNAS 98:5671–76 [Google Scholar]
  12. Ortlund EA, Bridgham JT, Redinbo MR, Thornton JW. 12.  2007. Crystal structure of an ancient protein: evolution by conformational epistasis. Science 317:1544–48 [Google Scholar]
  13. Strahle U, Klock G, Schutz G. 13.  1987. A DNA sequence of 15 base pairs is sufficient to mediate both glucocorticoid and progesterone induction of gene expression. PNAS 84:7871–75 [Google Scholar]
  14. Surjit M, Ganti KP, Mukherji A, Ye T, Hua G. 14.  et al. 2011. Widespread negative response elements mediate direct repression by agonist-liganded glucocorticoid receptor. Cell 145:224–41 [Google Scholar]
  15. Hudson WH, Youn C, Ortlund EA. 15.  2013. The structural basis of direct glucocorticoid-mediated transrepression. Nat. Struct. Mol. Biol. 20:53–58 [Google Scholar]
  16. Luisi BF, Xu WX, Otwinowski Z, Freedman LP, Yamamoto KR, Sigler PB. 16.  1991. Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA. Nature 352:497–505 [Google Scholar]
  17. Hudson WH, Youn C, Ortlund EA. 17.  2014. Crystal structure of the mineralocorticoid receptor DNA binding domain in complex with DNA. PLOS ONE 9:e107000 [Google Scholar]
  18. Jonat C, Rahmsdorf HJ, Park KK, Cato AC, Gebel S. 18.  et al. 1990. Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell 62:1189–204 [Google Scholar]
  19. Diamond MI, Miner JN, Yoshinaga SK, Yamamoto KR. 19.  1990. Transcription factor interactions: selectors of positive or negative regulation from a single DNA element. Science 249:1266–72 [Google Scholar]
  20. Garza AM, Khan SH, Kumar R. 20.  2010. Site-specific phosphorylation induces functionally active conformation in the intrinsically disordered N-terminal activation function (AF1) domain of the glucocorticoid receptor. Mol. Cell. Biol. 30:220–30 [Google Scholar]
  21. Arriza JL, Simerly RB, Swanson LW, Evans RM. 21.  1988. The neuronal mineralocorticoid receptor as a mediator of glucocorticoid response. Neuron 1:887–900 [Google Scholar]
  22. Rupprecht R, Arriza JL, Spengler D, Reul JM, Evans RM. 22.  et al. 1993. Transactivation and synergistic properties of the mineralocorticoid receptor: relationship to the glucocorticoid receptor. Mol. Endocrinol. 7:597–603 [Google Scholar]
  23. Taves MD, Plumb AW, Sandkam BA, Ma C, Van Der Gugten JG. 23.  et al. 2015. Steroid profiling reveals widespread local regulation of glucocorticoid levels during mouse development. Endocrinology 156:511–22 [Google Scholar]
  24. Hunter RW, Bailey MA. 24.  2015. Glucocorticoids and 11β-hydroxysteroid dehydrogenases: mechanisms for hypertension. Curr. Opin. Pharmacol. 21:105–14 [Google Scholar]
  25. Leliavski A, Dumbell R, Ott V, Oster H. 25.  2015. Adrenal clocks and the role of adrenal hormones in the regulation of circadian physiology. J. Biol. Rhythms 30:20–34 [Google Scholar]
  26. Lightman SL, Conway-Campbell BL. 26.  2010. The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration. Nat. Rev. Neurosci. 11:710–18 [Google Scholar]
  27. Ishida A, Mutoh T, Ueyama T, Bando H, Masubuchi S. 27.  et al. 2005. Light activates the adrenal gland: timing of gene expression and glucocorticoid release. Cell Metab. 2:297–307 [Google Scholar]
  28. Chung S, Son GH, Kim K. 28.  2011. Circadian rhythm of adrenal glucocorticoid: its regulation and clinical implications. Biochim. Biophys. Acta 1812:581–91 [Google Scholar]
  29. Son GH, Chung S, Choe HK, Kim HD, Baik SM. 29.  et al. 2008. Adrenal peripheral clock controls the autonomous circadian rhythm of glucocorticoid by causing rhythmic steroid production. PNAS 105:20970–75 [Google Scholar]
  30. Abe K, Kroning J, Greer MA, Critchlow V. 30.  1979. Effects of destruction of the suprachiasmatic nuclei on the circadian rhythms in plasma corticosterone, body temperature, feeding and plasma thyrotropin. Neuroendocrinology 29:119–31 [Google Scholar]
  31. Walker JJ, Terry JR, Lightman SL. 31.  2010. Origin of ultradian pulsatility in the hypothalamic-pituitary-adrenal axis. Proc. R. Soc. B 277:1627–33 [Google Scholar]
  32. Stavreva DA, Wiench M, John S, Conway-Campbell BL, McKenna MA. 32.  et al. 2009. Ultradian hormone stimulation induces glucocorticoid receptor–mediated pulses of gene transcription. Nat. Cell Biol. 11:1093–102 [Google Scholar]
  33. Conway-Campbell BL, George CL, Pooley JR, Knight DM, Norman MR. 33.  et al. 2011. The HSP90 molecular chaperone cycle regulates cyclical transcriptional dynamics of the glucocorticoid receptor and its coregulatory molecules CBP/p300 during ultradian ligand treatment. Mol. Endocrinol. 25:944–54 [Google Scholar]
  34. Conway-Campbell BL, Sarabdjitsingh RA, McKenna MA, Pooley JR, Kershaw YM. 34.  et al. 2010. Glucocorticoid ultradian rhythmicity directs cyclical gene pulsing of the clock gene period 1 in rat hippocampus. J. Neuroendocrinol. 22:1093–100 [Google Scholar]
  35. Stavreva DA, Coulon A, Baek S, Sung MH, John S. 35.  et al. 2015. Dynamics of chromatin accessibility and long-range interactions in response to glucocorticoid pulsing. Genome Res. 25:845–57 [Google Scholar]
  36. Henley DE, Russell GM, Douthwaite JA, Wood SA, Buchanan F. 36.  et al. 2009. Hypothalamic-pituitary-adrenal axis activation in obstructive sleep apnea: the effect of continuous positive airway pressure therapy. J. Clin. Endocrinol. Metab. 94:4234–42 [Google Scholar]
  37. Windle RJ, Wood SA, Kershaw YM, Lightman SL, Ingram CD, Harbuz MS. 37.  2008. Increased corticosterone pulse frequency during adjuvant-induced arthritis and its relationship to alterations in stress responsiveness. J. Neuroendocrinol. 13:905–11 [Google Scholar]
  38. Henley DE, Lightman SL. 38.  2014. Cardio-metabolic consequences of glucocorticoid replacement: relevance of ultradian signalling. Clin. Endocrinol. 80:621–28 [Google Scholar]
  39. Fardet L, Fève B. 39.  2014. Systemic glucocorticoid therapy: a review of its metabolic and cardiovascular adverse events. Drugs 74:1731–45 [Google Scholar]
  40. Robblee JP, Miura MT, Bain DL. 40.  2012. Glucocorticoid receptor–promoter interactions: Energetic dissection suggests a framework for the specificity of steroid receptor–mediated gene regulation. Biochemistry 51:4463–72 [Google Scholar]
  41. Nagaich AK, Walker DA, Wolford R, Hager GL. 41.  2004. Rapid periodic binding and displacement of the glucocorticoid receptor during chromatin remodeling. Mol. Cell 14:163–74 [Google Scholar]
  42. Stavreva DA, Muller WG, Hager GL, Smith CL, McNally JG. 42.  2004. Rapid glucocorticoid receptor exchange at a promoter is coupled to transcription and regulated by chaperones and proteasomes. Mol. Cell. Biol. 24:2682–97 [Google Scholar]
  43. Ong KM, Blackford JA Jr, Kagan BL, Simons SS Jr, Chow CC. 43.  2010. A theoretical framework for gene induction and experimental comparisons. PNAS 107:7107–12 [Google Scholar]
  44. Schiller BJ, Chodankar R, Watson LC, Stallcup MR, Yamamoto KR. 44.  2014. Glucocorticoid receptor binds half sites as a monomer and regulates specific target genes. Genome Biol. 15:418 [Google Scholar]
  45. Starick SR, Ibn-Salem J, Jurk M, Hernandez C, Love MI. 45.  et al. 2015. ChIP-exo signal associated with DNA-binding motifs provides insight into the genomic binding of the glucocorticoid receptor and cooperating transcription factors. Genome Res. 25:825–35 [Google Scholar]
  46. Lim HW, Uhlenhaut NH, Rauch A, Weiner J, Hubner S. 46.  et al. 2015. Genomic redistribution of GR monomers and dimers mediates transcriptional response to exogenous glucocorticoid in vivo. Genome Res. 25:836–44 [Google Scholar]
  47. Digman MA, Dalal R, Horwitz AF, Gratton E. 47.  2008. Mapping the number of molecules and brightness in the laser scanning microscope. Biophys. J. 94:2320–32 [Google Scholar]
  48. Presman DM, Ogara MF, Stortz M, Alvarez LD, Pooley JR. 48.  et al. 2014. Live cell imaging unveils multiple domain requirements for in vivo dimerization of the glucocorticoid receptor. PLOS Biol. 12:e1001813 [Google Scholar]
  49. Gebhardt JC, Suter DM, Roy R, Zhao ZW, Chapman AR. 49.  et al. 2013. Single-molecule imaging of transcription factor binding to DNA in live mammalian cells. Nat. Methods 10:421–26 [Google Scholar]
  50. Meijsing SH, Pufall MA, So AY, Bates DL, Chen L, Yamamoto KR. 50.  2009. DNA binding site sequence directs glucocorticoid receptor structure and activity. Science 324:407–10 [Google Scholar]
  51. Watson LC, Kuchenbecker KM, Schiller BJ, Gross JD, Pufall MA, Yamamoto KR. 51.  2013. The glucocorticoid receptor dimer interface allosterically transmits sequence-specific DNA signals. Nat. Struct. Mol. Biol. 20:876–83 [Google Scholar]
  52. Kassel O, Herrlich P. 52.  2007. Crosstalk between the glucocorticoid receptor and other transcription factors: molecular aspects. Mol. Cell. Endocrinol. 275:13–29 [Google Scholar]
  53. Ratman D, Vanden Berghe W, Dejager L, Libert C, Tavernier J. 53.  et al. 2013. How glucocorticoid receptors modulate the activity of other transcription factors: a scope beyond tethering. Mol. Cell. Endocrinol. 380:41–54 [Google Scholar]
  54. Cooper CD, Newman JA, Gileadi O. 54.  2014. Recent advances in the structural molecular biology of Ets transcription factors: interactions, interfaces and inhibition. Biochem. Soc. Trans. 42:130–38 [Google Scholar]
  55. Vinson C, Acharya A, Taparowsky EJ. 55.  2006. Deciphering B-ZIP transcription factor interactions in vitro and in vivo. Biochim. Biophys. Acta 1759:4–12 [Google Scholar]
  56. Wan F, Lenardo MJ. 56.  2009. Specification of DNA binding activity of NF-κB proteins. Cold Spring Harb. Perspect. Biol. 1:a000067 [Google Scholar]
  57. Lelli KM, Slattery M, Mann RS. 57.  2012. Disentangling the many layers of eukaryotic transcriptional regulation. Annu. Rev. Genet. 46:43–68 [Google Scholar]
  58. Chinenov Y, Gupte R, Rogatsky I. 58.  2013. Nuclear receptors in inflammation control: repression by GR and beyond. Mol. Cell. Endocrinol. 380:55–64 [Google Scholar]
  59. Engblom D, Kornfeld JW, Schwake L, Tronche F, Reimann A. 59.  et al. 2007. Direct glucocorticoid receptor–Stat5 interaction in hepatocytes controls body size and maturation-related gene expression. Genes Dev. 21:1157–62 [Google Scholar]
  60. Guo L, Lichten LA, Ryu MS, Liuzzi JP, Wang F, Cousins RJ. 60.  2010. STAT5–glucocorticoid receptor interaction and MTF-1 regulate the expression of ZnT2 (Slc30a2) in pancreatic acinar cells. PNAS 107:2818–23 [Google Scholar]
  61. Rogatsky I, Wang JC, Derynck MK, Nonaka DF, Khodabakhsh DB. 61.  et al. 2003. Target-specific utilization of transcriptional regulatory surfaces by the glucocorticoid receptor. PNAS 100:13845–50 [Google Scholar]
  62. Rogatsky I, Luecke HF, Leitman DC, Yamamoto KR. 62.  2002. Alternate surfaces of transcriptional coregulator GRIP1 function in different glucocorticoid receptor activation and repression contexts. PNAS 99:16701–6 [Google Scholar]
  63. Luecke HF, Yamamoto KR. 63.  2005. The glucocorticoid receptor blocks P-TEFb recruitment by NFκB to effect promoter-specific transcriptional repression. Genes Dev. 19:1116–27 [Google Scholar]
  64. Gupte R, Muse GW, Chinenov Y, Adelman K, Rogatsky I. 64.  2013. Glucocorticoid receptor represses proinflammatory genes at distinct steps of the transcription cycle. PNAS 110:14616–21 [Google Scholar]
  65. Langlais D, Couture C, Balsalobre A, Drouin J. 65.  2012. The Stat3/GR interaction code: predictive value of direct/indirect DNA recruitment for transcription outcome. Mol. Cell 47:38–49 [Google Scholar]
  66. Berg OG, Winter RB, von Hippel PH. 66.  1981. Diffusion-driven mechanisms of protein translocation on nucleic acids. 1. Models and theory. Biochemistry 20:6929–48 [Google Scholar]
  67. Chen J, Zhang Z, Li L, Chen BC, Revyakin A. 67.  et al. 2014. Single-molecule dynamics of enhanceosome assembly in embryonic stem cells. Cell 156:1274–85 [Google Scholar]
  68. Polman JA, Hunter RG, Speksnijder N, van den Oever JM, Korobko OB. 68.  et al. 2012. Glucocorticoids modulate the mTOR pathway in the hippocampus: differential effects depending on stress history. Endocrinology 153:4317–27 [Google Scholar]
  69. Reddy TE, Pauli F, Sprouse RO, Neff NF, Newberry KM. 69.  et al. 2009. Genomic determination of the glucocorticoid response reveals unexpected mechanisms of gene regulation. Genome Res. 19:2163–71 [Google Scholar]
  70. Rao NA, McCalman MT, Moulos P, Francoijs KJ, Chatziioannou A. 70.  et al. 2011. Coactivation of GR and NFKB alters the repertoire of their binding sites and target genes. Genome Res. 21:1404–16 [Google Scholar]
  71. Park SG, Hannenhalli S, Choi SS. 71.  2014. Conservation in first introns is positively associated with the number of exons within genes and the presence of regulatory epigenetic signals. BMC Genomics 15:526 [Google Scholar]
  72. John S, Sabo PJ, Thurman RE, Sung MH, Biddie SC. 72.  et al. 2011. Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nat. Genet. 43:264–68 [Google Scholar]
  73. Tang Q, Chen Y, Meyer C, Geistlinger T, Lupien M. 73.  et al. 2011. A comprehensive view of nuclear receptor cancer cistromes. Cancer Res. 71:6940–47 [Google Scholar]
  74. Grontved L, John S, Baek S, Liu Y, Buckley JR. 74.  et al. 2013. C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements. EMBO J. 32:1568–83 [Google Scholar]
  75. Reddy TE, Gertz J, Crawford GE, Garabedian MJ, Myers RM. 75.  2012. The hypersensitive glucocorticoid response specifically regulates Period 1 and expression of circadian genes. Mol. Cell. Biol. 32:3756–67 [Google Scholar]
  76. Biddie SC, John S, Sabo PJ, Thurman RE, Johnson TA. 76.  et al. 2011. Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol. Cell 43:145–55 [Google Scholar]
  77. Uhlenhaut NH, Barish GD, Yu RT, Downes M, Karunasiri M. 77.  et al. 2013. Insights into negative regulation by the glucocorticoid receptor from genome-wide profiling of inflammatory cistromes. Mol. Cell 49:158–71 [Google Scholar]
  78. Steger DJ, Grant GR, Schupp M, Tomaru T, Lefterova MI. 78.  et al. 2010. Propagation of adipogenic signals through an epigenomic transition state. Genes Dev. 24:1035–44 [Google Scholar]
  79. Rhee HS, Pugh BF. 79.  2011. Comprehensive genome-wide protein-DNA interactions detected at single-nucleotide resolution. Cell 147:1408–19 [Google Scholar]
  80. Serandour AA, Brown GD, Cohen JD, Carroll JS. 80.  2013. Development of an Illumina-based ChIP-exonuclease method provides insight into FoxA1-DNA binding properties. Genome Biol. 14:R147 [Google Scholar]
  81. Simons SS Jr, Kumar R. 81.  2013. Variable steroid receptor responses: Intrinsically disordered AF1 is the key. Mol. Cell. Endocrinol. 376:81–84 [Google Scholar]
  82. Stashi E, York B, O'Malley BW. 82.  2014. Steroid receptor coactivators: servants and masters for control of systems metabolism. Trends Endocrinol. Metab. 25:337–47 [Google Scholar]
  83. Rollins DA, Coppo M, Rogatsky I. 83.  2015. Minireview: nuclear receptor coregulators of the p160 family: insights into inflammation and metabolism. Mol. Endocrinol. 29:502–17 [Google Scholar]
  84. Marmorstein R, Zhou MM. 84.  2014. Writers and readers of histone acetylation: structure, mechanism, and inhibition. Cold Spring Harb. Perspect. Biol. 6:a018762 [Google Scholar]
  85. Duan K, Gomez Hernandez K, Mete O. 85.  2015. Clinicopathological correlates of adrenal Cushing's syndrome. J. Clin. Pathol. 68:175–86 [Google Scholar]
  86. Raff H, Carroll T. 86.  2015. Cushing's syndrome: from physiological principles to diagnosis and clinical care. J. Physiol. 593:493–506 [Google Scholar]
  87. van Raalte DH, Brands M, van der Zijl NJ, Muskiet MH, Pouwels PJW. 87.  et al. 2011. Low-dose glucocorticoid treatment affects multiple aspects of intermediary metabolism in healthy humans: a randomised controlled trial. Diabetologia 54:2103–12 [Google Scholar]
  88. Kauh E, Mixson L, Malice MP, Mesens S, Ramael S. 88.  et al. 2011. Prednisone affects inflammation, glucose tolerance, and bone turnover within hours of treatment in healthy individuals. Eur. J. Endocrinol. 166:459–67 [Google Scholar]
  89. Burt MG, Willenberg VM, Petersons CJ, Smith MD, Ahern MJ, Stranks SN. 89.  2012. Screening for diabetes in patients with inflammatory rheumatological disease administered long-term prednisolone: a cross-sectional study. Rheumatology 51:1112–19 [Google Scholar]
  90. Asrih M, Jornayvaz FR. 90.  2015. Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?. Mol. Cell. Endocrinol. 41855–65
  91. Kowalski GM, Bruce CR. 91.  2014. The regulation of glucose metabolism: implications and considerations for the assessment of glucose homeostasis in rodents. Am. J. Physiol. Endocrinol. Metab. 307:E859–71 [Google Scholar]
  92. Rafacho A, Ortsater H, Nadal A, Quesada I. 92.  2014. Glucocorticoid treatment and endocrine pancreas function: implications for glucose homeostasis, insulin resistance and diabetes. J. Endocrinol. 223:R49–62 [Google Scholar]
  93. Cole TJ, Blendy JA, Monaghan AP, Krieglstein K, Schmid W. 93.  et al. 1995. Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation. Genes Dev. 9:1608–21 [Google Scholar]
  94. Jitrapakdee S. 94.  2012. Transcription factors and coactivators controlling nutrient and hormonal regulation of hepatic gluconeogenesis. Int. J. Biochem. Cell Biol. 44:33–45 [Google Scholar]
  95. Opherk C, Tronche F, Kellendonk C, Kohlmüller D, Schulze A. 95.  et al. 2004. Inactivation of the glucocorticoid receptor in hepatocytes leads to fasting hypoglycemia and ameliorates hyperglycemia in streptozotocin-induced diabetes mellitus. Mol. Endocrinol. 18:1346–53 [Google Scholar]
  96. Rose AJ, Herzig S. 96.  2013. Metabolic control through glucocorticoid hormones: an update. Mol. Cell. Endocrinol. 380:65–78 [Google Scholar]
  97. Liang Y, Osborne MC, Monia BP, Bhanot S, Watts LM. 97.  et al. 2005. Antisense oligonucleotides targeted against glucocorticoid receptor reduce hepatic glucose production and ameliorate hyperglycemia in diabetic mice. Metabolism 54:848–55 [Google Scholar]
  98. Jacobson PB. 98.  2005. Hepatic glucocorticoid receptor antagonism is sufficient to reduce elevated hepatic glucose output and improve glucose control in animal models of type 2 diabetes. J. Pharmacol. Exp. Ther. 314:191–200 [Google Scholar]
  99. Yang J, Reshef L, Cassuto H, Aleman G, Hanson RW. 99.  2009. Aspects of the control of phosphoenolpyruvate carboxykinase gene transcription. J. Biol. Chem. 284:27031–35 [Google Scholar]
  100. Bernal-Mizrachi C, Weng S, Feng C, Finck BN, Knutsen RH. 100.  et al. 2003. Dexamethasone induction of hypertension and diabetes is PPAR-α dependent in LDL receptor–null mice. Nat. Med. 9:1069–75 [Google Scholar]
  101. Boergesen M, Pedersen TA, Gross B, van Heeringen SJ, Hagenbeek D. 101.  et al. 2012. Genome-wide profiling of liver X receptor, retinoid X receptor, and peroxisome proliferator–activated receptor α in mouse liver reveals extensive sharing of binding sites. Mol. Cell. Biol. 32:852–67 [Google Scholar]
  102. Lee JM, Wagner M, Xiao R, Kim KH, Feng D. 102.  et al. 2014. Nutrient-sensing nuclear receptors coordinate autophagy. Nature 516:112–15 [Google Scholar]
  103. Patel R, Patel M, Tsai R, Lin V, Bookout AL. 103.  et al. 2011. LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice. J. Clin. Investig. 121:431–41 [Google Scholar]
  104. Renga B, Mencarelli A, D'Amore C, Cipriani S, Baldelli F. 104.  et al. 2012. Glucocorticoid receptor mediates the gluconeogenic activity of the farnesoid X receptor in the fasting condition. FASEB J. 26:3021–31 [Google Scholar]
  105. Liu S, Croniger C, Arizmendi C, Harada-Shiba M, Ren J. 105.  et al. 1999. Hypoglycemia and impaired hepatic glucose production in mice with a deletion of the C/EBPβ gene. J. Clin. Investig. 103:207–13 [Google Scholar]
  106. Arnaldi G, Scandali VM, Trementino L, Cardinaletti M, Appolloni G, Boscaro M. 106.  2010. Pathophysiology of dyslipidemia in Cushing's syndrome. Neuroendocrinology 92:86–90 [Google Scholar]
  107. Rockall A, Sohaib S, Evans D, Kaltsas G, Isidori A. 107.  et al. 2003. Hepatic steatosis in Cushing's syndrome: a radiological assessment using computed tomography. Eur. J. Endocrinol. 149:543–48 [Google Scholar]
  108. Lemke U, Krones-Herzig A, Diaz MB, Narvekar P, Ziegler A. 108.  et al. 2008. The glucocorticoid receptor controls hepatic dyslipidemia through Hes1. Cell Metab. 8:212–23 [Google Scholar]
  109. Revollo JR, Oakley RH, Lu NZ, Kadmiel M, Gandhavadi M, Cidlowski JA. 109.  2013. HES1 is a master regulator of glucocorticoid receptor–dependent gene expression. Sci. Signal. 6:ra103 [Google Scholar]
  110. Peckett AJ, Wright DC, Riddell MC. 110.  2011. The effects of glucocorticoids on adipose tissue lipid metabolism. Metabolism 60:1500–10 [Google Scholar]
  111. Fain JN, Kovacev VP, Scow RO. 111.  1965. Effect of growth hormone and dexamethasone on lipolysis and metabolism in isolated fat cells of the rat. J. Biol. Chem. 240:3522–29 [Google Scholar]
  112. Samra JS, Clark ML, Humphreys SM, MacDonald IA, Bannister PA, Frayn KN. 112.  1998. Effects of physiological hypercortisolemia on the regulation of lipolysis in subcutaneous adipose tissue. J. Clin. Endocrinol. Metab. 83:626–31 [Google Scholar]
  113. Lee MJ, Pramyothin P, Karastergiou K, Fried SK. 113.  2014. Deconstructing the roles of glucocorticoids in adipose tissue biology and the development of central obesity. Biochim. Biophys. Acta 1842:473–81 [Google Scholar]
  114. Rebuffe-Scrive M, Krotkiewski M, Elfverson J, Bjorntorp P. 114.  1988. Muscle and adipose tissue morphology and metabolism in Cushing's syndrome. J. Clin. Endocrinol. Metab. 67:1122–28 [Google Scholar]
  115. Yu CY, Mayba O, Lee JV, Tran J, Harris C. 115.  et al. 2010. Genome-wide analysis of glucocorticoid receptor binding regions in adipocytes reveal gene network involved in triglyceride homeostasis. PLOS ONE 5:e15188 [Google Scholar]
  116. Asada M, Rauch A, Shimizu H, Maruyama H, Miyaki S. 116.  et al. 2010. DNA binding–dependent glucocorticoid receptor activity promotes adipogenesis via Krüppel-like factor 15 gene expression. Lab. Investig. 91:203–15 [Google Scholar]
  117. Laudet V, Lahnalampi M, Heinäniemi M, Sinkkonen L, Wabitsch M, Carlberg C. 117.  2010. Time-resolved expression profiling of the nuclear receptor superfamily in human adipogenesis. PLOS ONE5:e12991
  118. Mikkelsen TS, Xu Z, Zhang X, Wang L, Gimble JM. 118.  et al. 2010. Comparative epigenomic analysis of murine and human adipogenesis. Cell 143:156–69 [Google Scholar]
  119. Siersbaek R, Nielsen R, John S, Sung MH, Baek S. 119.  et al. 2011. Extensive chromatin remodelling and establishment of transcription factor ‘hotspots’ during early adipogenesis. EMBO J. 30:1459–72 [Google Scholar]
  120. Kang S, Tsai LT, Zhou Y, Evertts A, Xu S. 120.  et al. 2015. Identification of nuclear hormone receptor pathways causing insulin resistance by transcriptional and epigenomic analysis. Nat. Cell Biol. 17:44–56 [Google Scholar]
  121. Kuo T, Harris CA, Wang J-C. 121.  2013. Metabolic functions of glucocorticoid receptor in skeletal muscle. Mol. Cell. Endocrinol. 380:79–88 [Google Scholar]
  122. Lofberg E, Gutierrez A, Wernerman J, Anderstam B, Mitch WE. 122.  et al. 2002. Effects of high doses of glucocorticoids on free amino acids, ribosomes and protein turnover in human muscle. Eur. J. Clin. Investig. 32:345–53 [Google Scholar]
  123. Braun TP, Zhu X, Szumowski M, Scott GD, Grossberg AJ. 123.  et al. 2011. Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic-pituitary-adrenal axis. J. Exp. Med. 208:2449–63 [Google Scholar]
  124. Short KR, Bigelow ML, Nair KS. 124.  2009. Short-term prednisone use antagonizes insulin's anabolic effect on muscle protein and glucose metabolism in young healthy people. Am. J. Physiol. Endocrinol. Metab. 297:E1260–68 [Google Scholar]
  125. Laplante M, Sabatini DM. 125.  2012. mTOR signaling in growth control and disease. Cell 149:274–93 [Google Scholar]
  126. Schiaffino S, Mammucari C. 126.  2011. Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models. Skelet. Muscle 1:4 [Google Scholar]
  127. Yamazaki Y, Kamei Y, Sugita S, Akaike F, Kanai S. 127.  et al. 2010. The cathepsin L gene is a direct target of FOXO1 in skeletal muscle. Biochem. J. 427:171–78 [Google Scholar]
  128. Schakman O, Kalista S, Barbe C, Loumaye A, Thissen JP. 128.  2013. Glucocorticoid-induced skeletal muscle atrophy. Int. J. Biochem. Cell Biol. 45:2163–72 [Google Scholar]
  129. Kuo T, Lew MJ, Mayba O, Harris CA, Speed TP, Wang JC. 129.  2012. Genome-wide analysis of glucocorticoid receptor–binding sites in myotubes identifies gene networks modulating insulin signaling. PNAS 109:11160–65 [Google Scholar]
  130. Watson ML, Baehr LM, Reichardt HM, Tuckermann JP, Bodine SC, Furlow JD. 130.  2012. A cell-autonomous role for the glucocorticoid receptor in skeletal muscle atrophy induced by systemic glucocorticoid exposure. Am. J. Physiol. Endocrinol. Metab. 302:E1210–20 [Google Scholar]
  131. Waddell DS, Baehr LM, van den Brandt J, Johnsen SA, Reichardt HM. 131.  et al. 2008. The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy–associated MuRF1 gene. Am. J. Physiol. Endocrinol. Metab. 295:E785–97 [Google Scholar]
  132. Shimizu N, Yoshikawa N, Ito N, Maruyama T, Suzuki Y. 132.  et al. 2011. Crosstalk between glucocorticoid receptor and nutritional sensor mTOR in skeletal muscle. Cell Metab. 13:170–82 [Google Scholar]
  133. Lutzner N, Kalbacher H, Krones-Herzig A, Rosl F. 133.  2012. FOXO3 is a glucocorticoid receptor target and regulates LKB1 and its own expression based on cellular AMP levels via a positive autoregulatory loop. PLOS ONE 7:e42166 [Google Scholar]
  134. Wang H, Kubica N, Ellisen LW, Jefferson LS, Kimball SR. 134.  2006. Dexamethasone represses signaling through the mammalian target of rapamycin in muscle cells by enhancing expression of REDD1. J. Biol. Chem. 281:39128–34 [Google Scholar]
  135. Britto FA, Begue G, Rossano B, Docquier A, Vernus B. 135.  et al. 2014. REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy. Am. J. Physiol. Endocrinol. Metab. 307:E983–93 [Google Scholar]
  136. Kagan JC, Barton GM. 136.  2015. Emerging principles governing signal transduction by pattern-recognition receptors. Cold Spring Harb. Perspect. Biol. 7:a016253 [Google Scholar]
  137. Matzinger P. 137.  2002. The danger model: a renewed sense of self. Science 296:301–5 [Google Scholar]
  138. Besedovsky H, Sorkin E, Keller M, Muller J. 138.  1975. Changes in blood hormone levels during the immune response. Proc. Soc. Exp. Biol. Med. 150:466–70 [Google Scholar]
  139. Bhattacharyya S, Brown DE, Brewer JA, Vogt SK, Muglia LJ. 139.  2007. Macrophage glucocorticoid receptors regulate Toll-like receptor 4–mediated inflammatory responses by selective inhibition of p38 MAP kinase. Blood 109:4313–19 [Google Scholar]
  140. Goodwin JE, Feng Y, Velazquez H, Sessa WC. 140.  2013. Endothelial glucocorticoid receptor is required for protection against sepsis. PNAS 110:306–11 [Google Scholar]
  141. Sevilla LM, Latorre V, Sanchis A, Perez P. 141.  2013. Epidermal inactivation of the glucocorticoid receptor triggers skin barrier defects and cutaneous inflammation. J. Investig. Dermatol. 133:361–70 [Google Scholar]
  142. Oakley RH, Ren R, Cruz-Topete D, Bird GS, Myers PH. 142.  et al. 2013. Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease. PNAS 110:17035–40 [Google Scholar]
  143. Oppong E, Flink N, Cato AC. 143.  2013. Molecular mechanisms of glucocorticoid action in mast cells. Mol. Cell. Endocrinol. 380:119–26 [Google Scholar]
  144. Zen M, Canova M, Campana C, Bettio S, Nalotto L. 144.  et al. 2011. The kaleidoscope of glucorticoid effects on immune system. Autoimmun. Rev. 10:305–10 [Google Scholar]
  145. Vandevyver S, Dejager L, Van Bogaert T, Kleyman A, Liu Y. 145.  et al. 2012. Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation. J. Clin. Investig. 122:2130–40 [Google Scholar]
  146. Bereshchenko O, Coppo M, Bruscoli S, Biagioli M, Cimino M. 146.  et al. 2014. GILZ promotes production of peripherally induced Treg cells and mediates the crosstalk between glucocorticoids and TGF-β signaling. Cell Rep. 7:464–75 [Google Scholar]
  147. Altonsy MO, Sasse SK, Phang TL, Gerber AN. 147.  2014. Context-dependent cooperation between nuclear factor κB (NF-κB) and the glucocorticoid receptor at a TNFAIP3 intronic enhancer: a mechanism to maintain negative feedback control of inflammation. J. Biol. Chem. 289:8231–39 [Google Scholar]
  148. Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS Jr. 148.  1995. Role of transcriptional activation of IκBα in mediation of immunosuppression by glucocorticoids. Science 270:283–86 [Google Scholar]
  149. Yang YH, Aeberli D, Dacumos A, Xue JR, Morand EF. 149.  2009. Annexin-1 regulates macrophage IL-6 and TNF via glucocorticoid-induced leucine zipper. J. Immunol. 183:1435–45 [Google Scholar]
  150. Chinenov Y, Coppo M, Gupte R, Sacta MA, Rogatsky I. 150.  2014. Glucocorticoid receptor coordinates transcription factor–dominated regulatory network in macrophages. BMC Genomics 15:656 [Google Scholar]
  151. Vandevyver S, Dejager L, Tuckermann J, Libert C. 151.  2013. New insights into the anti-inflammatory mechanisms of glucocorticoids: an emerging role for glucocorticoid-receptor-mediated transactivation. Endocrinology 154:993–1007 [Google Scholar]
  152. Abraham SM, Lawrence T, Kleiman A, Warden P, Medghalchi M. 152.  et al. 2006. Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1. J. Exp. Med. 203:1883–89 [Google Scholar]
  153. Chi H, Barry SP, Roth RJ, Wu JJ, Jones EA. 153.  et al. 2006. Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses. PNAS 103:2274–79 [Google Scholar]
  154. Maier JV, Brema S, Tuckermann J, Herzer U, Klein M. 154.  et al. 2007. Dual specificity phosphatase 1 knockout mice show enhanced susceptibility to anaphylaxis but are sensitive to glucocorticoids. Mol. Endocrinol. 21:2663–71 [Google Scholar]
  155. Beaulieu E, Morand EF. 155.  2011. Role of GILZ in immune regulation, glucocorticoid actions and rheumatoid arthritis. Nat. Rev. Rheumatol. 7:340–48 [Google Scholar]
  156. De Bosscher K, Beck IM, Dejager L, Bougarne N, Gaigneaux A. 156.  et al. 2014. Selective modulation of the glucocorticoid receptor can distinguish between transrepression of NF-κB and AP-1. Cell. Mol. Life Sci. 71:143–63 [Google Scholar]
  157. Rogatsky I, Zarember KA, Yamamoto KR. 157.  2001. Factor recruitment and TIF2/GRIP1 corepressor activity at a collagenase-3 response element that mediates regulation by phorbol esters and hormones. EMBO J. 20:6071–83 [Google Scholar]
  158. Chinenov Y, Gupte R, Dobrovolna J, Flammer JR, Liu B. 158.  et al. 2012. Role of transcriptional coregulator GRIP1 in the anti-inflammatory actions of glucocorticoids. PNAS 109:11776–81 [Google Scholar]
  159. Gilchrist DA, Fromm G, dos Santos G, Pham LN, McDaniel IE. 159.  et al. 2012. Regulating the regulators: the pervasive effects of Pol II pausing on stimulus-responsive gene networks. Genes Dev. 26:933–44 [Google Scholar]
  160. Adelman K, Kennedy MA, Nechaev S, Gilchrist DA, Muse GW. 160.  et al. 2009. Immediate mediators of the inflammatory response are poised for gene activation through RNA polymerase II stalling. PNAS 106:18207–12 [Google Scholar]
  161. Diefenbacher M, Sekula S, Heilbock C, Maier JV, Litfin M. 161.  et al. 2008. Restriction to Fos family members of Trip6-dependent coactivation and glucocorticoid receptor–dependent trans-repression of activator protein-1. Mol. Endocrinol. 22:1767–80 [Google Scholar]
  162. Diefenbacher ME, Reich D, Dahley O, Kemler D, Litfin M. 162.  et al. 2014. The LIM domain protein nTRIP6 recruits the mediator complex to AP-1-regulated promoters. PLOS ONE 9:e97549 [Google Scholar]
  163. Chen SH, Masuno K, Cooper SB, Yamamoto KR. 163.  2013. Incoherent feed-forward regulatory logic underpinning glucocorticoid receptor action. PNAS 110:1964–69 [Google Scholar]
/content/journals/10.1146/annurev-physiol-021115-105323
Loading
/content/journals/10.1146/annurev-physiol-021115-105323
Loading

Data & Media loading...

Supplemental Material

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error