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. 1993 Oct;92(4):1896–1902. doi: 10.1172/JCI116782

Evidence of direct estrogenic regulation of human corticotropin-releasing hormone gene expression. Potential implications for the sexual dimophism of the stress response and immune/inflammatory reaction.

N C Vamvakopoulos 1, G P Chrousos 1
PMCID: PMC288355  PMID: 8408641

Abstract

Corticotropin-releasing hormone (CRH) plays major roles in coordination of the stress response and regulation of the immune/inflammatory reaction, two important functions associated with sexual dimorphism. Two overlapping segments of the 5' flanking region of the human (h) CRH gene, the proximal 0.9 kb (containing two perfect half-palindromic estrogen-responsive elements [EREs]) and the 2.4 kb (including the former and containing two additional perfect half-palindromic EREs), were examined for their ability to confer estrogen-mediated transcriptional enhancement to a homologous or heterologous promoter. The level of estrogen-induced transactivation by the 0.9- and 2.4-kb segments was determined by chloramphenicol acetyltransferase analysis in CV-1 cells cotransfected with estrogen receptor (ER) cDNA expression plasmids, and found to be respectively approximately 10% and 20% of that of the strongly estrogen-responsive Xenopus vitellogenin A2 enhancer. Gel retardation and immunoprecipitation demonstrated specific association between the perfect half-palindromic EREs of hCRH gene and the DNA binding domain of hER in vitro. These findings may constitute the basis of sexual dimorphism in the expression of the CRH gene in the central nervous system and periphery, and might shed light in existing gender differences in stress response and immune regulation.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahima R. S., Lawson A. N., Osei S. Y., Harlan R. E. Sexual dimorphism in regulation of type II corticosteroid receptor immunoreactivity in the rat hippocampus. Endocrinology. 1992 Sep;131(3):1409–1416. doi: 10.1210/endo.131.3.1505471. [DOI] [PubMed] [Google Scholar]
  2. Allen J. B., Blatter D., Calandra G. B., Wilder R. L. Sex hormonal effects on the severity of streptococcal cell wall-induced polyarthritis in the rat. Arthritis Rheum. 1983 Apr;26(4):560–563. doi: 10.1002/art.1780260418. [DOI] [PubMed] [Google Scholar]
  3. Angel P., Imagawa M., Chiu R., Stein B., Imbra R. J., Rahmsdorf H. J., Jonat C., Herrlich P., Karin M. Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell. 1987 Jun 19;49(6):729–739. doi: 10.1016/0092-8674(87)90611-8. [DOI] [PubMed] [Google Scholar]
  4. Bateman A., Singh A., Kral T., Solomon S. The immune-hypothalamic-pituitary-adrenal axis. Endocr Rev. 1989 Feb;10(1):92–112. doi: 10.1210/edrv-10-1-92. [DOI] [PubMed] [Google Scholar]
  5. Beato M. Gene regulation by steroid hormones. Cell. 1989 Feb 10;56(3):335–344. doi: 10.1016/0092-8674(89)90237-7. [DOI] [PubMed] [Google Scholar]
  6. Berkenbosch F., Wolvers D. A., Derijk R. Neuroendocrine and immunological mechanisms in stress-induced immunomodulation. J Steroid Biochem Mol Biol. 1991;40(4-6):639–647. doi: 10.1016/0960-0760(91)90286-e. [DOI] [PubMed] [Google Scholar]
  7. Bohler H. C., Jr, Zoeller R. T., King J. C., Rubin B. S., Weber R., Merriam G. R. Corticotropin releasing hormone mRNA is elevated on the afternoon of proestrus in the parvocellular paraventricular nuclei of the female rat. Brain Res Mol Brain Res. 1990 Aug;8(3):259–262. doi: 10.1016/0169-328x(90)90025-9. [DOI] [PubMed] [Google Scholar]
  8. Burgess L. H., Handa R. J. Chronic estrogen-induced alterations in adrenocorticotropin and corticosterone secretion, and glucocorticoid receptor-mediated functions in female rats. Endocrinology. 1992 Sep;131(3):1261–1269. doi: 10.1210/endo.131.3.1324155. [DOI] [PubMed] [Google Scholar]
  9. Butler P. D., Weiss J. M., Stout J. C., Nemeroff C. B. Corticotropin-releasing factor produces fear-enhancing and behavioral activating effects following infusion into the locus coeruleus. J Neurosci. 1990 Jan;10(1):176–183. doi: 10.1523/JNEUROSCI.10-01-00176.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chappell P. B., Smith M. A., Kilts C. D., Bissette G., Ritchie J., Anderson C., Nemeroff C. B. Alterations in corticotropin-releasing factor-like immunoreactivity in discrete rat brain regions after acute and chronic stress. J Neurosci. 1986 Oct;6(10):2908–2914. doi: 10.1523/JNEUROSCI.06-10-02908.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chrousos G. P., Gold P. W. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA. 1992 Mar 4;267(9):1244–1252. [PubMed] [Google Scholar]
  12. Chrousos G. P. Regulation and dysregulation of the hypothalamic-pituitary-adrenal axis. The corticotropin-releasing hormone perspective. Endocrinol Metab Clin North Am. 1992 Dec;21(4):833–858. [PubMed] [Google Scholar]
  13. Crofford L. J., Sano H., Karalis K., Webster E. L., Goldmuntz E. A., Chrousos G. P., Wilder R. L. Local secretion of corticotropin-releasing hormone in the joints of Lewis rats with inflammatory arthritis. J Clin Invest. 1992 Dec;90(6):2555–2564. doi: 10.1172/JCI116150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. De Souza E. B., Insel T. R., Perrin M. H., Rivier J., Vale W. W., Kuhar M. J. Corticotropin-releasing factor receptors are widely distributed within the rat central nervous system: an autoradiographic study. J Neurosci. 1985 Dec;5(12):3189–3203. doi: 10.1523/JNEUROSCI.05-12-03189.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Dunn A. J., Berridge C. W. Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses? Brain Res Brain Res Rev. 1990 May-Aug;15(2):71–100. doi: 10.1016/0165-0173(90)90012-d. [DOI] [PubMed] [Google Scholar]
  16. Ferin M., Van Vugt D., Wardlaw S. The hypothalamic control of the menstrual cycle and the role of endogenous opioid peptides. Recent Prog Horm Res. 1984;40:441–485. doi: 10.1016/b978-0-12-571140-1.50015-3. [DOI] [PubMed] [Google Scholar]
  17. Ghosh D. A relational database of transcription factors. Nucleic Acids Res. 1990 Apr 11;18(7):1749–1756. doi: 10.1093/nar/18.7.1749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gold P. W., Goodwin F. K., Chrousos G. P. Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress (2) N Engl J Med. 1988 Aug 18;319(7):413–420. doi: 10.1056/NEJM198808183190706. [DOI] [PubMed] [Google Scholar]
  19. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Green S., Issemann I., Sheer E. A versatile in vivo and in vitro eukaryotic expression vector for protein engineering. Nucleic Acids Res. 1988 Jan 11;16(1):369–369. doi: 10.1093/nar/16.1.369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Green S. Nuclear hormone receptors. Promiscuous liaisons. Nature. 1993 Feb 18;361(6413):590–591. doi: 10.1038/361590a0. [DOI] [PubMed] [Google Scholar]
  22. Grino M., Chrousos G. P., Margioris A. N. The corticotropin releasing hormone gene is expressed in human placenta. Biochem Biophys Res Commun. 1987 Nov 13;148(3):1208–1214. doi: 10.1016/s0006-291x(87)80261-9. [DOI] [PubMed] [Google Scholar]
  23. Grossman C. J., Roselle G. A., Mendenhall C. L. Sex steroid regulation of autoimmunity. J Steroid Biochem Mol Biol. 1991;40(4-6):649–659. doi: 10.1016/0960-0760(91)90287-f. [DOI] [PubMed] [Google Scholar]
  24. Haleem D. J., Kennett G., Curzon G. Adaptation of female rats to stress: shift to male pattern by inhibition of corticosterone synthesis. Brain Res. 1988 Aug 23;458(2):339–347. doi: 10.1016/0006-8993(88)90476-3. [DOI] [PubMed] [Google Scholar]
  25. Harrison S. C. A structural taxonomy of DNA-binding domains. Nature. 1991 Oct 24;353(6346):715–719. doi: 10.1038/353715a0. [DOI] [PubMed] [Google Scholar]
  26. Homo-Delarche F., Fitzpatrick F., Christeff N., Nunez E. A., Bach J. F., Dardenne M. Sex steroids, glucocorticoids, stress and autoimmunity. J Steroid Biochem Mol Biol. 1991;40(4-6):619–637. doi: 10.1016/0960-0760(91)90285-d. [DOI] [PubMed] [Google Scholar]
  27. Hutchens T. W., Allen M. H. Differences in the conformational state of a zinc-finger DNA-binding protein domain occupied by zinc and copper revealed by electrospray ionization mass spectrometry. Rapid Commun Mass Spectrom. 1992 Jul;6(7):469–473. doi: 10.1002/rcm.1290060713. [DOI] [PubMed] [Google Scholar]
  28. Irwin M., Vale W., Rivier C. Central corticotropin-releasing factor mediates the suppressive effect of stress on natural killer cytotoxicity. Endocrinology. 1990 Jun;126(6):2837–2844. doi: 10.1210/endo-126-6-2837. [DOI] [PubMed] [Google Scholar]
  29. Karalis K., Sano H., Redwine J., Listwak S., Wilder R. L., Chrousos G. P. Autocrine or paracrine inflammatory actions of corticotropin-releasing hormone in vivo. Science. 1991 Oct 18;254(5030):421–423. doi: 10.1126/science.1925600. [DOI] [PubMed] [Google Scholar]
  30. Kato S., Tora L., Yamauchi J., Masushige S., Bellard M., Chambon P. A far upstream estrogen response element of the ovalbumin gene contains several half-palindromic 5'-TGACC-3' motifs acting synergistically. Cell. 1992 Feb 21;68(4):731–742. doi: 10.1016/0092-8674(92)90148-6. [DOI] [PubMed] [Google Scholar]
  31. Klein-Hitpass L., Ryffel G. U., Heitlinger E., Cato A. C. A 13 bp palindrome is a functional estrogen responsive element and interacts specifically with estrogen receptor. Nucleic Acids Res. 1988 Jan 25;16(2):647–663. doi: 10.1093/nar/16.2.647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Klein-Hitpass L., Schorpp M., Wagner U., Ryffel G. U. An estrogen-responsive element derived from the 5' flanking region of the Xenopus vitellogenin A2 gene functions in transfected human cells. Cell. 1986 Sep 26;46(7):1053–1061. doi: 10.1016/0092-8674(86)90705-1. [DOI] [PubMed] [Google Scholar]
  33. Melia K. R., Duman R. S. Involvement of corticotropin-releasing factor in chronic stress regulation of the brain noradrenergic system. Proc Natl Acad Sci U S A. 1991 Oct 1;88(19):8382–8386. doi: 10.1073/pnas.88.19.8382. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Munck A., Guyre P. M., Holbrook N. J. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev. 1984 Winter;5(1):25–44. doi: 10.1210/edrv-5-1-25. [DOI] [PubMed] [Google Scholar]
  35. Otten A. D., Sanders M. M., McKnight G. S. The MMTV LTR promoter is induced by progesterone and dihydrotestosterone but not by estrogen. Mol Endocrinol. 1988 Feb;2(2):143–147. doi: 10.1210/mend-2-2-143. [DOI] [PubMed] [Google Scholar]
  36. Pelletier G., Liao N., Follea N., Govindan M. V. Mapping of estrogen receptor-producing cells in the rat brain by in situ hybridization. Neurosci Lett. 1988 Nov 22;94(1-2):23–28. doi: 10.1016/0304-3940(88)90264-9. [DOI] [PubMed] [Google Scholar]
  37. Rivier C. L., Plotsky P. M. Mediation by corticotropin releasing factor (CRF) of adenohypophysial hormone secretion. Annu Rev Physiol. 1986;48:475–494. doi: 10.1146/annurev.ph.48.030186.002355. [DOI] [PubMed] [Google Scholar]
  38. Rivier C., Vale W. Effect of the long-term administration of corticotropin-releasing factor on the pituitary-adrenal and pituitary-gonadal axis in the male rat. J Clin Invest. 1985 Feb;75(2):689–694. doi: 10.1172/JCI111748. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Robinson B. G., Emanuel R. L., Frim D. M., Majzoub J. A. Glucocorticoid stimulates expression of corticotropin-releasing hormone gene in human placenta. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5244–5248. doi: 10.1073/pnas.85.14.5244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Schwabe J. W., Rhodes D. Beyond zinc fingers: steroid hormone receptors have a novel structural motif for DNA recognition. Trends Biochem Sci. 1991 Aug;16(8):291–296. doi: 10.1016/0968-0004(91)90121-b. [DOI] [PubMed] [Google Scholar]
  41. Shivers B. D., Harlan R. E., Morrell J. I., Pfaff D. W. Absence of oestradiol concentration in cell nuclei of LHRH-immunoreactive neurones. 1983 Jul 28-Aug 3Nature. 304(5924):345–347. doi: 10.1038/304345a0. [DOI] [PubMed] [Google Scholar]
  42. Staudt L. M., Singh H., Sen R., Wirth T., Sharp P. A., Baltimore D. A lymphoid-specific protein binding to the octamer motif of immunoglobulin genes. Nature. 1986 Oct 16;323(6089):640–643. doi: 10.1038/323640a0. [DOI] [PubMed] [Google Scholar]
  43. Sternberg E. M., Hill J. M., Chrousos G. P., Kamilaris T., Listwak S. J., Gold P. W., Wilder R. L. Inflammatory mediator-induced hypothalamic-pituitary-adrenal axis activation is defective in streptococcal cell wall arthritis-susceptible Lewis rats. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2374–2378. doi: 10.1073/pnas.86.7.2374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Sternberg E. M., Young W. S., 3rd, Bernardini R., Calogero A. E., Chrousos G. P., Gold P. W., Wilder R. L. A central nervous system defect in biosynthesis of corticotropin-releasing hormone is associated with susceptibility to streptococcal cell wall-induced arthritis in Lewis rats. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4771–4775. doi: 10.1073/pnas.86.12.4771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Su T. P., London E. D., Jaffe J. H. Steroid binding at sigma receptors suggests a link between endocrine, nervous, and immune systems. Science. 1988 Apr 8;240(4849):219–221. doi: 10.1126/science.2832949. [DOI] [PubMed] [Google Scholar]
  46. Swanson L. W., Sawchenko P. E., Rivier J., Vale W. W. Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study. Neuroendocrinology. 1983;36(3):165–186. doi: 10.1159/000123454. [DOI] [PubMed] [Google Scholar]
  47. Swanson L. W., Simmons D. M. Differential steroid hormone and neural influences on peptide mRNA levels in CRH cells of the paraventricular nucleus: a hybridization histochemical study in the rat. J Comp Neurol. 1989 Jul 22;285(4):413–435. doi: 10.1002/cne.902850402. [DOI] [PubMed] [Google Scholar]
  48. Traish A. M., Ettinger R., Kim N., Marshak-Rothstein A., Wotiz H. H. Development and characterization of monoclonal antibodies to a specific domain of human estrogen receptor. Steroids. 1990 May;55(5):196–208. doi: 10.1016/0039-128x(90)90017-6. [DOI] [PubMed] [Google Scholar]
  49. Vale W., Spiess J., Rivier C., Rivier J. Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science. 1981 Sep 18;213(4514):1394–1397. doi: 10.1126/science.6267699. [DOI] [PubMed] [Google Scholar]
  50. Vamvakopoulos N. C., Chrousos G. P. Regulated activity of the distal promoter-like element of the human corticotropin-releasing hormone gene and secondary structural features of its corresponding transcripts. Mol Cell Endocrinol. 1993 Jul;94(1):73–78. doi: 10.1016/0303-7207(93)90053-m. [DOI] [PubMed] [Google Scholar]
  51. Vamvakopoulos N. C., Mayol V., Margioris A. N., Chrousos G. P. Lack of dexamethasone modulation of mRNAs involved in the glucocorticoid signal transduction pathway in two cell systems. Steroids. 1992 Jun;57(6):282–287. doi: 10.1016/0039-128x(92)90061-d. [DOI] [PubMed] [Google Scholar]
  52. Wilder R. L., Calandra G. B., Garvin A. J., Wright K. D., Hansen C. T. Strain and sex variation in the susceptibility to streptococcal cell wall-induced polyarthritis in the rat. Arthritis Rheum. 1982 Sep;25(9):1064–1072. doi: 10.1002/art.1780250906. [DOI] [PubMed] [Google Scholar]
  53. Wilson T. E., Paulsen R. E., Padgett K. A., Milbrandt J. Participation of non-zinc finger residues in DNA binding by two nuclear orphan receptors. Science. 1992 Apr 3;256(5053):107–110. doi: 10.1126/science.1314418. [DOI] [PubMed] [Google Scholar]
  54. Yen S. S., Lein A. The apparent paradox of the negative and positive feedback control system on gonadotropin secretion. Am J Obstet Gynecol. 1976 Dec 1;126(7):942–954. doi: 10.1016/0002-9378(76)90681-5. [DOI] [PubMed] [Google Scholar]

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