A novel point mutation in the ligand-binding domain (LBD) of the human glucocorticoid receptor (hGR) causing generalized glucocorticoid resistance: The importance of the C terminus of hGR LBD in conferring transactivational activity

Journal of Clinical Endocrinology and Metabolism

Volumn 90, Issue 6, 2005, Pages 3696-3705

  Charmandari, Evangelia ^a,c   Raji, Annaswamy ^b   Kino, Tomoshige ^a   Ichijo, Takamasa ^a   Tiulpakov, Anatoly ^a   Zachman, Keith ^a   Chrousos, George P ^a  

^a EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT   (United States)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

^c GREAT ORMOND STREET HOSPITAL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

DEXAMETHASONE; GLUCOCORTICOID; GLUCOCORTICOID RECEPTOR; LIGAND; PRIMER DNA; THYMIDINE;

ADULT; AMINO ACID SUBSTITUTION; ANAMNESIS; ANIMAL CELL; ANXIETY; ARTICLE; CARBOXY TERMINAL SEQUENCE; CASE REPORT; CLINICAL EXAMINATION; DNA BINDING; DRUG MEGADOSE; FATIGUE; FEMALE; GENE MUTATION; HETEROZYGOSITY; HORMONE RESISTANCE; HUMAN; HUMAN CELL; HYPERANDROGENISM; HYPERTENSION; LABORATORY TEST; LIGAND BINDING; MOLECULAR INTERACTION; MOLECULAR MECHANICS; MOUSE MAMMARY TUMOR ONCOVIRUS; NONHUMAN; POINT MUTATION; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN DOMAIN; PROTEIN LOCALIZATION; SIGNAL TRANSDUCTION; TRANSACTIVATION; WILD TYPE; ANIMAL; BINDING SITE; CELL LINE; CELL STRAIN COS1; CERCOPITHECUS; DRUG EFFECT; DRUG RESISTANCE; GENETIC TRANSFECTION; GENETICS; METABOLISM; PHYSIOLOGY; REPORTER GENE; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION;

MOUSE MAMMARY TUMOR VIRUS;

ADULT; ANIMALS; BINDING SITES; CELL LINE; CERCOPITHECUS AETHIOPS; COS CELLS; DEXAMETHASONE; DNA PRIMERS; DRUG RESISTANCE; FEMALE; GENES, REPORTER; GLUCOCORTICOIDS; HUMANS; LIGANDS; POINT MUTATION; RECEPTORS, GLUCOCORTICOID; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; THYMIDINE; TRANS-ACTIVATION (GENETICS); TRANSFECTION;

EID: 21244432841     PISSN: 0021972X     EISSN: 0021972X     Source Type: Journal    
DOI: 10.1210/jc.2004-1920     Document Type: Article

References (48)

1. Chrousos GP, Vingerhoeds A, Brandon D, Eil C, Pugeat M, DeVroede M, Loriaux DL, Lipsett MB 1982 Primary cortisol resistance in man. A glucocorticoid receptor-mediated disease. J Clin Invest 69:1261-1269
2. Chrousos GP, Detera-Wadleigh SD, Karl M 1993 Syndromes of glucocorticoid resistance. Ann Intern Med 119:1113-1124
3. Kino T, Vottero A, Charmandari E, Chrousos GP 2002 Familial/sporadic glucocorticoid resistance syndrome and hypertension. Ann NY Acad Sci 970:101-111
4. Kino T, De Martino MU, Charmandari E, Mirani M, Chrousos GP 2003 Tissue glucocorticoid resistance/hypersensitivity syndromes. J Steroid Biochem Mol Biol 85:457-467
5. Charmandari E, Kino T, Chrousos GP 2004 Familial/sporadic glucocorticoid resistance: clinical phenotype and molecular mechanisms. Ann NY Acad Sci 1024:168-181
6. Hurley DM, Accili D, Stratakis CA, Karl M, Vamvakopoulos N, Rorer E, Constantine K, Taylor SI, Chrousos GP 1991 Point mutation causing a single amino acid substitution in the hormone-binding domain of the glucocorticoid receptor in familial glucocorticoid resistance. J Clin Invest 87:680-686
7. Karl M, Lamberts SW, Detera-Wadleigh SD, Encio IJ, Stratakis CA, Hurley DM, Accili D, Chrousos GP 1993 Familial glucocorticoid resistance caused by a splice site deletion in the human glucocorticoid receptor gene. J Clin Endocrinol Metab 76:683-689
8. Karl M, Lamberts SW, Koper JW, Katz DA, Huizenga NE, Kino T, Haddad BR, Hughes MR, Chrousos GP 1996 Cushing's disease preceded by generalized glucocorticoid resistance: clinical consequences of a novel, dominantnegative glucocorticoid receptor mutation. Proc Assoc Am Physicians 108:296-307
9. Malchoff DM, Brufsky A, Reardon G, McDermott P, Javier EC, Bergh CH, Rowe D, Malchoff CD 1993 A mutation of the glucocorticoid receptor in primary cortisol resistance. J Clin Invest 91:1918-1925
10. Ruiz M, Lind U, Gafvels M, Eggertsen G, Carlstedt-Duke J, Nilsson L, Holtmann M, Stierna P, Wikstrom AC, Werner S 2001 Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance. Clin Endocrinol (Oxf) 55:363-371
11. Kino T, Stauber RH, Resau JH, Pavlakis GN, Chrousos GP 2001 Pathologic human GR mutant has a transdominant negative effect on the wild-type GR by inhibiting its translocation into the nucleus: importance of the ligandbinding domain for intracellular GR trafficking. J Clin Endocrinol Metab 86:5600-5608
12. Mendonca BB, Leite MV, de Castro M, Kino T, Elias LL, Bachega TA, Arnhold IJ, Chrousos GP, Latronico AC 2002 Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene. J Clin Endocrinol Metab 87:1805-1809
13. Vottero A, Kino T, Combe H, Lecomte P, Chrousos GP 2002 A novel, C-terminal dominant negative mutation of the GR causes familial glucocorticoid resistance through abnormal interactions with p160 steroid receptor coactivators. J Clin Endocrinol Metab 87:2658-2667
14. Charmandari E, Kino T, Souvatzoglou E, Vottero A, Bhattacharyya N, Chrousos GP 2004 Natural glucocorticoid receptor mutants causing generalized glucocorticoid resistance: molecular genotype, genetic transmission, and clinical phenotype. J Clin Endocrinol Metab 89:1939-1949
15. Pratt WB 1993 The role of heat shock proteins in regulating the function, folding, and trafficking of the glucocorticoid receptor. J Biol Chem 268:21455-21458
16. Bamberger CM, Schulte HM, Chrousos GP 1996 Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr Rev 17:245-261
17. Jonat C, Rahmsdorf HJ, Park KK, Cato AC, Gebel S, Ponta H, Herrlich P 1990 Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell 62:1189-1204
18. Scheinman RI, Gualberto A, Jewell CM, Cidlowski JA, Baldwin Jr AS 1995 Characterization of mechanisms involved in transrepression of NF-κB by activated glucocorticoid receptors. Mol Cell Biol 15:943-953
19. Hollenberg SM, Evans RM 1988 Multiple and cooperative transactivation domains of the human glucocorticoid receptor. Cell 55:899-906
20. McKenna NJ, Lanz RB, O'Malley BW 1999 Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 20:321-344
21. McKenna NJ, Xu J, Nawaz Z, Tsai SY, Tsai MJ, O'Malley BW 1999 Nuclear receptor coactivators: multiple enzymes, multiple complexes, multiple functions. J Steroid Biochem Mol Biol 69:3-12
22. McKenna NJ, O'Malley BW 2002 Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 108:465-474
23. Auboeuf D, Honig A, Berget SM, O'Malley BW 2002 Coordinate regulation of transcription and splicing by steroid receptor coregulators. Science 298:416-419
24. Tomita M, Brandon DD, Chrousos GP, Vingerhoeds AC, Foster CM, Fowler D, Loriaux DL, Lipsett MB 1986 Glucocorticoid receptors in Epstein-Barr virus-transformed lymphocytes from patients with glucocorticoid resistance and a glucocorticoid-resistant New World primate species. J Clin Endocrinol Metab 62:1145-1154
25. Kino T, Slobodskaya O, Pavlakis GN, Chrousos GP 2002 Nuclear receptor coactivator p160 proteins enhance the HIV-1 long terminal repeat promoter by bridging promoter-bound factors and the Tat-P-TEFb complex. J Biol Chem 277:2396-2405
26. Felgner PL, Gadek TR, Holm M, Roman R, Chan HW, Wenz M, Northrop JP, Ringold GM, Danielsen M 1987 Lipofection: a highly efficient, lipidmediated DNA-transfection procedure. Proc Natl Acad Sci USA 84:7413-7417
27. Brasier AR, Tate JE, Habener JF 1989 Optimized use of the firefly luciferase assay as a reporter gene in mammalian cell lines. Biotechniques 7:1116-1122
28. Stauber RH, Horie K, Carney P, Hudson EA, Tarasova NI, Gaitanaris GA, Pavlakis GN 1998 Development and applications of enhanced green fluorescent protein mutants. Biotechniques 24:462-471
29. Bhattacharyya N, Dey A, Minucci S, Zimmer A, John S, Hager G, Ozato K 1997 Retinoid-induced chromatin structure alterations in the retinoic acid receptor β2 promoter. Mol Cell Biol 17:6481-6490
30. Kino T, Gragerov A, Kopp JB, Stauber RH, Pavlakis GN, Chrousos GP 1999 The HIV-1 virion-associated protein Vpr is a coactivator of the human glucocorticoid receptor. J Exp Med 1 89:51-62
31. Bledsoe RK, Montana VG, Stanley TB, Delves CJ, Apolito CJ, McKee DD, Consler TG, Parks DJ, Stewart EL, Willson TM, Lambert MH, Moore JT, Pearce KH, Xu HE 2002 Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell 110:93-105
32. Ding XF, Anderson CM, Ma H, Hong H, Uht RM, Kushner PJ, Stallcup MR 1998 Nuclear receptor-binding sites of coactivators glucocorticoid receptor interacting protein 1 (GRIP1) and steroid receptor coactivator 1 (SRC-1): multiple motifs with different binding specificities. Mol Endocrinol 12:302-313
33. Hong H, Kohli K, Garabedian MJ, Stallcup MR 1997 GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors. Mol Cell Biol 17:2735-2744
34. Hong H, Kohli K, Trivedi A, Johnson DL, Stallcup MR 1996 GRIP1, a novel mouse protein that serves as a transcriptional coactivator in yeast for the hormone binding domains of steroid receptors. Proc Natl Acad Sci USA 93:4948-4952
35. Refetoff S, Weiss RE, Usala SJ 1993 The syndromes of resistance to thyroid hormone. Endocr Rev 14:348-399
36. Vegeto E, Shahbaz MM, Wen DX, Goldman ME, O'Malley BW, McDonnell DP 1993 Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function. Mol Endocrinol 7:1244-1255
37. Bamberger CM, Bamberger AM, de Castro M, Chrousos GP 1995 Glucocorticoid receptor β, a potential endogenous inhibitor of glucocorticoid action in humans. J Clin Invest 95:2435-2441
38. Oakley RH, Jewell CM, Yudt MR, Bofetiado DM, Cidlowski JA 1999 The dominant negative activity of the human glucocorticoid receptor β isoform. Specificity and mechanisms of action. J Biol Chem 274:27857-27866
39. Charmandari E, Chrousos GP, Ichijo T, Bhattacharyya N, Vottero A, Souvatzoglou E, Kino T 2005 The human glucocorticoid receptor (hGR) β isoform suppresses the transcriptional activity of hGRα by interfering with formation of active coactivator complexes. Mol Endocrinol 19:52-64
40. Zhang S, Liang X, Danielsen M 1996 Role of the C terminus of the glucocorticoid receptor in hormone binding and agonist/antagonist discrimination. Mol Endocrinol 10:24-34
41. Kauppi B, Jakob C, Farnegardh M, Yang J, Ahola H, Alarcon M, Calles K, Engstrom O, Harlan J, Muchmore S, Ramqvist AK, Thorell S, Ohman L, Greer J, Gustafsson JA, Carlstedt-Duke J, Carlquist M 2003 The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain: RU-486 induces a transconformation that leads to active antagonism. J Biol Chem 278:22748-22754
42. Savory JG, Hsu B, Laquian IR, Giffin W, Reich T, Hache RJ, Lefebvre YA 1999 Discrimination between NL1- and NL2-mediated nuclear localization of the glucocorticoid receptor. Mol Cell Biol 19:1025-1037
43. Picard D, Yamamoto KR 1987 Two signals mediate hormone-dependent nuclear localization of the glucocorticoid receptor. EMBO J 6:3333-3340
44. Qi M, Hamilton BJ, DeFranco D 1989 v-Mos oncoproteins affect the nuclear retention and reutilization of glucocorticoid receptors. Mol Endocrinol 3:1279-1288
45. Wikstrom AC, Bakke O, Okret S, Bronnegard M, Gustafsson JA 1987 Intracellular localization of the glucocorticoid receptor: evidence for cytoplasmic and nuclear localization. Endocrinology 120:1232-1242
46. Gold PW, Chrousos GP 2002 Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry 7:254-275
47. Gold PW, Chrousos GP 1999 The endocrinology of melancholic and atypical depression: relation to neurocircuitry and somatic consequences. Proc Assoc Am Physicians 111:22-34
48. Charmandari E, Merke DP, Negro PJ, Keil MF, Martinez PE, Haim A, Gold PW, Chrousos GP 2004 Endocrinologic and psychologic evaluation of 21-hydroxylase deficiency carriers and matched normal subjects: evidence for physical and/or psychologic vulnerability to stress. J Clin Endocrinol Metab 89:2228-2236