Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1989 Jun;83(6):2093–2101. doi: 10.1172/JCI114122

Selective expression of a normal action of the 1,25-dihydroxyvitamin D3 receptor in human skin fibroblasts with hereditary severe defects in multiple actions of that receptor.

J Barsony 1, W McKoy 1, D A DeGrange 1, U A Liberman 1, S J Marx 1
PMCID: PMC303936  PMID: 2542381

Abstract

We evaluated three actions of 1,25-dihydroxycholecalciferol [1,25-(OH)2D3] in human skin fibroblasts to test for heterogeneity in hormone-response coupling. In fibroblasts from normal subjects the 1,25-(OH)2D3 concentrations for half-maximal effect (EC50) were: for mitogenic effect 0.0001-0.0005 nM, for antimitogenic effect 1 nM, and for induction of 25-OHD3 24-hydroxylase (24-OHase) 5 nM. To evaluate the effects of mutations presumed to be in the gene for the 1,25-(OH)2D3 receptor we examined cell lines representing four kindreds with hereditary resistance to 1,25-(OH)2D3 ("mutant" cell lines). In one mutant cell line all three 1,25-(OH)2D3 actions were severely abnormal. In one mutant cell line 24-OHase induction and mitogenic action were undetectable, but EC50 and maximal effect were normal for antimitogenic action of 1,25-(OH)2D3. In two mutant cell lines 24-OHase induction and antimitogenic actions were undetectable or severely impaired but mitogenic action were undetectable or severely impaired but mitogenic action was normal in EC50 and normal or increased in maximal effect. The mitogenic and antimitogenic actions in normal cells showed a similar profile of potency ratios for 1,25-(OH)2D3 and six analogues. Whenever a mutant cell showed a normal or even an abnormal mitogenic or antimitogenic effect of 1,25-(OH)2D3, these effects showed potency ratios similar to wild type, suggesting mediation by a similar 1,25-(OH)2D3 receptor. We conclude that three 1,25-(OH)2D3 actions show important differences in hormone response coupling indicated by differences in EC50 for 1,25-(OH)2D3 and by different consequences of receptor mutations.

Full text

PDF
2093

Selected References

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

  1. Adler S., Waterman M. L., He X., Rosenfeld M. G. Steroid receptor-mediated inhibition of rat prolactin gene expression does not require the receptor DNA-binding domain. Cell. 1988 Mar 11;52(5):685–695. doi: 10.1016/0092-8674(88)90406-0. [DOI] [PubMed] [Google Scholar]
  2. Bliziotes M., Yergey A. L., Nanes M. S., Muenzer J., Begley M. G., Vieira N. E., Kher K. K., Brandi M. L., Marx S. J. Absent intestinal response to calciferols in hereditary resistance to 1,25-dihydroxyvitamin D: documentation and effective therapy with high dose intravenous calcium infusions. J Clin Endocrinol Metab. 1988 Feb;66(2):294–300. doi: 10.1210/jcem-66-2-294. [DOI] [PubMed] [Google Scholar]
  3. Catterall J. F., Kontula K. K., Watson C. S., Seppänen P. J., Funkenstein B., Melanitou E., Hickok N. J., Bardin C. W., Jänne O. A. Regulation of gene expression by androgens in murine kidney. Recent Prog Horm Res. 1986;42:71–109. doi: 10.1016/b978-0-12-571142-5.50006-9. [DOI] [PubMed] [Google Scholar]
  4. Chen T. L., Hauschka P. V., Feldman D. Dexamethasone increases 1,25-dihydroxyvitamin D3 receptor levels and augments bioresponses in rat osteoblast-like cells. Endocrinology. 1986 Mar;118(3):1119–1126. doi: 10.1210/endo-118-3-1119. [DOI] [PubMed] [Google Scholar]
  5. Clemens T. L., Adams J. S., Horiuchi N., Gilchrest B. A., Cho H., Tsuchiya Y., Matsuo N., Suda T., Holick M. F. Interaction of 1,25-dihydroxyvitamin-D3 with keratinocytes and fibroblasts from skin of normal subjects and a subject with vitamin-D-dependent rickets, type II: a model for study of the mode of action of 1,25-dihydroxyvitamin D3. J Clin Endocrinol Metab. 1983 Apr;56(4):824–830. doi: 10.1210/jcem-56-4-824. [DOI] [PubMed] [Google Scholar]
  6. Cordingley M. G., Riegel A. T., Hager G. L. Steroid-dependent interaction of transcription factors with the inducible promoter of mouse mammary tumor virus in vivo. Cell. 1987 Jan 30;48(2):261–270. doi: 10.1016/0092-8674(87)90429-6. [DOI] [PubMed] [Google Scholar]
  7. DeFranco D., Yamamoto K. R. Two different factors act separately or together to specify functionally distinct activities at a single transcriptional enhancer. Mol Cell Biol. 1986 Apr;6(4):993–1001. doi: 10.1128/mcb.6.4.993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dosquet-Bernard C., Wilhelm F., Lomri N., Tobelem G., Caen J. P. 1 alpha, 25-dihydroxyvitamin D3 modulates the growth of 3T3 cells and human skin fibroblasts stimulated by platelet-derived growth factor. Cell Biol Int Rep. 1986 Dec;10(12):931–938. doi: 10.1016/0309-1651(86)90113-x. [DOI] [PubMed] [Google Scholar]
  9. Dubik D., Shiu R. P. Transcriptional regulation of c-myc oncogene expression by estrogen in hormone-responsive human breast cancer cells. J Biol Chem. 1988 Sep 5;263(25):12705–12708. [PubMed] [Google Scholar]
  10. Eisman J. A., Frampton R. J., McLean F. J. Biochemical significance of enhanced activity of fluorinated 1,25-dihydroxyvitamin D3 in human cultured cell lines. Cell Biochem Funct. 1986 Apr;4(2):115–122. doi: 10.1002/cbf.290040207. [DOI] [PubMed] [Google Scholar]
  11. Evans R. M. The steroid and thyroid hormone receptor superfamily. Science. 1988 May 13;240(4854):889–895. doi: 10.1126/science.3283939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Freake H. C., Marcocci C., Iwasaki J., MacIntyre I. 1,25-dihydroxyvitamin D3 specifically binds to a human breast cancer cell line (T47D) and stimulates growth. Biochem Biophys Res Commun. 1981 Aug 31;101(4):1131–1138. doi: 10.1016/0006-291x(81)91565-5. [DOI] [PubMed] [Google Scholar]
  13. Gamblin G. T., Liberman U. A., Eil C., Downs R. W., Jr, DeGrange D. A., Marx S. J. Vitamin D-dependent rickets type II. Defective induction of 25-hydroxyvitamin D3-24-hydroxylase by 1,25-dihydroxyvitamin D3 in cultured skin fibroblasts. J Clin Invest. 1985 Mar;75(3):954–960. doi: 10.1172/JCI111796. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jantzen H. M., Strähle U., Gloss B., Stewart F., Schmid W., Boshart M., Miksicek R., Schütz G. Cooperativity of glucocorticoid response elements located far upstream of the tyrosine aminotransferase gene. Cell. 1987 Apr 10;49(1):29–38. doi: 10.1016/0092-8674(87)90752-5. [DOI] [PubMed] [Google Scholar]
  15. Klein E. S., Reinke R., Feigelson P., Ringold G. M. Glucocorticoid-regulated expression from the 5'-flanking region of the rat alpha 1-acid glycoprotein gene. Requirement for ongoing protein synthesis. J Biol Chem. 1987 Jan 15;262(2):520–523. [PubMed] [Google Scholar]
  16. Koren R., Ravid A., Liberman U. A., Hochberg Z., Weisman Y., Novogrodsky A. Defective binding and function of 1,25-dihydroxyvitamin D3 receptors in peripheral mononuclear cells of patients with end-organ resistance to 1,25-dihydroxyvitamin D. J Clin Invest. 1985 Nov;76(5):2012–2015. doi: 10.1172/JCI112201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lacey D. L., Axelrod J., Chappel J. C., Kahn A. J., Teitelbaum S. L. Vitamin D affects proliferation of a murine T helper cell clone. J Immunol. 1987 Mar 15;138(6):1680–1686. [PubMed] [Google Scholar]
  18. Lee Y., Dunlap B. E., Mellon W. S. Induction of monocytic differentiation by calcitriol (1,25-dihydroxyvitamin D3) in the human promyelocytic leukemic cell line (HL-60) in serum-free medium. Biochem Pharmacol. 1987 Nov 15;36(22):3893–3901. doi: 10.1016/0006-2952(87)90455-2. [DOI] [PubMed] [Google Scholar]
  19. Liberman U. A., Eil C., Marx S. J. Receptor-positive hereditary resistance to 1,25-dihydroxyvitamin D: chromatography of hormone-receptor complexes on deoxyribonucleic acid-cellulose shows two classes of mutation. J Clin Endocrinol Metab. 1986 Jan;62(1):122–126. doi: 10.1210/jcem-62-1-122. [DOI] [PubMed] [Google Scholar]
  20. Liberman U. A., Eil C., Marx S. J. Resistance to 1,25-dihydroxyvitamin D. Association with heterogeneous defects in cultured skin fibroblasts. J Clin Invest. 1983 Feb;71(2):192–200. doi: 10.1172/JCI110759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Majeska R. J., Rodan G. A. The effect of 1,25(OH)2D3 on alkaline phosphatase in osteoblastic osteosarcoma cells. J Biol Chem. 1982 Apr 10;257(7):3362–3365. [PubMed] [Google Scholar]
  22. Munker R., Norman A., Koeffler H. P. Vitamin D compounds. Effect on clonal proliferation and differentiation of human myeloid cells. J Clin Invest. 1986 Aug;78(2):424–430. doi: 10.1172/JCI112593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Okazaki T., Igarashi T., Kronenberg H. M. 5'-flanking region of the parathyroid hormone gene mediates negative regulation by 1,25-(OH)2 vitamin D3. J Biol Chem. 1988 Feb 15;263(5):2203–2208. [PubMed] [Google Scholar]
  24. Petkovich P. M., Wrana J. L., Grigoriadis A. E., Heersche J. N., Sodek J. 1,25-Dihydroxyvitamin D3 increases epidermal growth factor receptors and transforming growth factor beta-like activity in a bone-derived cell line. J Biol Chem. 1987 Oct 5;262(28):13424–13428. [PubMed] [Google Scholar]
  25. Quirk S. J., Funder J. W. Steroid receptors, and the generation of closely coupled/biphasic dose-response curves. J Steroid Biochem. 1988;30(1-6):9–15. doi: 10.1016/0022-4731(88)90070-2. [DOI] [PubMed] [Google Scholar]
  26. Rabindran S. K., Danielsen M., Stallcup M. R. Glucocorticoid-resistant lymphoma cell variants that contain functional glucocorticoid receptors. Mol Cell Biol. 1987 Dec;7(12):4211–4217. doi: 10.1128/mcb.7.12.4211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Santos G. F., Scott G. K., Lee W. M., Liu E., Benz C. Estrogen-induced post-transcriptional modulation of c-myc proto-oncogene expression in human breast cancer cells. J Biol Chem. 1988 Jul 15;263(20):9565–9568. [PubMed] [Google Scholar]
  28. Sasaki K., Chida K., Hashiba H., Kamata N., Abe E., Suda T., Kuroki T. Enhancement by 1 alpha,25-dihydroxyvitamin D3 of chemically induced transformation of BALB 3T3 cells without induction of ornithine decarboxylase or activation of protein kinase C1. Cancer Res. 1986 Feb;46(2):604–610. [PubMed] [Google Scholar]
  29. Skjødt H., Gallagher J. A., Beresford J. N., Couch M., Poser J. W., Russell R. G. Vitamin D metabolites regulate osteocalcin synthesis and proliferation of human bone cells in vitro. J Endocrinol. 1985 Jun;105(3):391–396. doi: 10.1677/joe.0.1050391. [DOI] [PubMed] [Google Scholar]
  30. Song M. K., Krutzsch H., Hankins W. D., Richards W. L., Thorgeirsson S. S. Rapid determination of DNA synthesis in adherent cells grown in microtiter plates. Exp Cell Res. 1985 Jan;156(1):271–276. doi: 10.1016/0014-4827(85)90281-2. [DOI] [PubMed] [Google Scholar]
  31. Spelsberg T. C., Goldberger A., Horton M., Hora J. Nuclear acceptor sites for sex steroid hormone receptors in chromatin. J Steroid Biochem. 1987;27(1-3):133–147. doi: 10.1016/0022-4731(87)90304-9. [DOI] [PubMed] [Google Scholar]
  32. Takigawa M., Enomoto M., Shirai E., Nishii Y., Suzuki F. Differential effects of 1 alpha,25-dihydroxycholecalciferol and 24R,25-dihydroxycholecalciferol on the proliferation and the differentiated phenotype of rabbit costal chondrocytes in culture. Endocrinology. 1988 Mar;122(3):831–839. doi: 10.1210/endo-122-3-831. [DOI] [PubMed] [Google Scholar]
  33. Theofan G., Nguyen A. P., Norman A. W. Regulation of calbindin-D28K gene expression by 1,25-dihydroxyvitamin D3 is correlated to receptor occupancy. J Biol Chem. 1986 Dec 25;261(36):16943–16947. [PubMed] [Google Scholar]
  34. Tora L., Gronemeyer H., Turcotte B., Gaub M. P., Chambon P. The N-terminal region of the chicken progesterone receptor specifies target gene activation. Nature. 1988 May 12;333(6169):185–188. doi: 10.1038/333185a0. [DOI] [PubMed] [Google Scholar]
  35. Van Wyk J. J., Graves D. C., Casella S. J., Jacobs S. Evidence from monoclonal antibody studies that insulin stimulates deoxyribonucleic acid synthesis through the type I somatomedin receptor. J Clin Endocrinol Metab. 1985 Oct;61(4):639–643. doi: 10.1210/jcem-61-4-639. [DOI] [PubMed] [Google Scholar]
  36. Wilhelm F., Norman A. W. Biochemical characterization of positive cooperativity in the binding of 1 alpha, 25-dihydroxyvitamin D3 to its chick intestinal chromatin receptor. J Biol Chem. 1985 Aug 25;260(18):10087–10092. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES