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. 1994 Apr;93(4):1370–1379. doi: 10.1172/JCI117113

Molecular mechanism of transcriptional activation of angiotensinogen gene by proximal promoter.

K Tamura 1, S Umemura 1, M Ishii 1, K Tanimoto 1, K Murakami 1, A Fukamizu 1
PMCID: PMC294149  PMID: 8163641

Abstract

Angiotensinogen is shown to be produced by the liver and the hepatoma cell line HepG2. As a first step for understanding the molecular relationship between the transcriptional regulation of the angiotensinogen gene and the pathogenesis of hypertension, we have analyzed the basal promoter of the angiotensinogen gene. Chloramphenicol acetyltransferase (CAT) assays with 5'-deleted constructs showed that the proximal promoter region from -96 to +22 of the transcriptional start site was enough to express HepG2-specific CAT activity. Electrophoretic mobility shift assay and DNase I footprinting demonstrated that the liver- and HepG2-specific nuclear factor (angiotensinogen gene-activating factor [AGF2]) and ubiquitous nuclear factor (AGF3) bound to the proximal promoter element from -96 to -52 (angiotensinogen gene-activating element [AGE2]) and to the core promoter element from -6 to +22 (AGE3), respectively. The site-directed disruption of either AGE2 or AGE3 decreased CAT expression, and the sequential titration of AGF3 binding by in vivo competition remarkably suppressed HepG2-specific CAT activity. Finally, the heterologous thymidine kinase promoter assay showed that AGE2 and AGE3 synergistically conferred HepG2-specific CAT expression. These results suggest that the synergistic interplay between AGF2 and AGF3 is important for the angiotensinogen promoter activation.

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Selected References

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

  1. Behrens J., Löwrick O., Klein-Hitpass L., Birchmeier W. The E-cadherin promoter: functional analysis of a G.C-rich region and an epithelial cell-specific palindromic regulatory element. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11495–11499. doi: 10.1073/pnas.88.24.11495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ben-Ari E. T., Lynch K. R., Garrison J. C. Glucocorticoids induce the accumulation of novel angiotensinogen gene transcripts. J Biol Chem. 1989 Aug 5;264(22):13074–13079. [PubMed] [Google Scholar]
  3. Brasier A. R., Ron D., Tate J. E., Habener J. F. A family of constitutive C/EBP-like DNA binding proteins attenuate the IL-1 alpha induced, NF kappa B mediated trans-activation of the angiotensinogen gene acute-phase response element. EMBO J. 1990 Dec;9(12):3933–3944. doi: 10.1002/j.1460-2075.1990.tb07614.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Brasier A. R., Tate J. E., Ron D., Habener J. F. Multiple cis-acting DNA regulatory elements mediate hepatic angiotensinogen gene expression. Mol Endocrinol. 1989 Jun;3(6):1022–1034. doi: 10.1210/mend-3-6-1022. [DOI] [PubMed] [Google Scholar]
  5. Briggs M. R., Kadonaga J. T., Bell S. P., Tjian R. Purification and biochemical characterization of the promoter-specific transcription factor, Sp1. Science. 1986 Oct 3;234(4772):47–52. doi: 10.1126/science.3529394. [DOI] [PubMed] [Google Scholar]
  6. Cambien F., Poirier O., Lecerf L., Evans A., Cambou J. P., Arveiler D., Luc G., Bard J. M., Bara L., Ricard S. Deletion polymorphism in the gene for angiotensin-converting enzyme is a potent risk factor for myocardial infarction. Nature. 1992 Oct 15;359(6396):641–644. doi: 10.1038/359641a0. [DOI] [PubMed] [Google Scholar]
  7. Cameron K. E., Resnik J., Webster N. J. Transcriptional regulation of the human insulin receptor promoter. J Biol Chem. 1992 Aug 25;267(24):17375–17383. [PubMed] [Google Scholar]
  8. Carter R. S., Bhat N. K., Basu A., Avadhani N. G. The basal promoter elements of murine cytochrome c oxidase subunit IV gene consist of tandemly duplicated ets motifs that bind to GABP-related transcription factors. J Biol Chem. 1992 Nov 15;267(32):23418–23426. [PubMed] [Google Scholar]
  9. Chen Y. F., Naftilan A. J., Oparil S. Androgen-dependent angiotensinogen and renin messenger RNA expression in hypertensive rats. Hypertension. 1992 May;19(5):456–463. doi: 10.1161/01.hyp.19.5.456. [DOI] [PubMed] [Google Scholar]
  10. Clouston W. M., Lyons I. G., Richards R. I. Tissue-specific and hormonal regulation of angiotensinogen minigenes in transgenic mice. EMBO J. 1989 Nov;8(11):3337–3343. doi: 10.1002/j.1460-2075.1989.tb08495.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cordingley M. G., Hager G. L. Binding of multiple factors to the MMTV promoter in crude and fractionated nuclear extracts. Nucleic Acids Res. 1988 Jan 25;16(2):609–628. doi: 10.1093/nar/16.2.609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Correa-Rotter R., Hostetter T. H., Rosenberg M. E. Renin and angiotensinogen gene expression in experimental diabetes mellitus. Kidney Int. 1992 Apr;41(4):796–804. doi: 10.1038/ki.1992.123. [DOI] [PubMed] [Google Scholar]
  13. Courtois G., Morgan J. G., Campbell L. A., Fourel G., Crabtree G. R. Interaction of a liver-specific nuclear factor with the fibrinogen and alpha 1-antitrypsin promoters. Science. 1987 Oct 30;238(4827):688–692. doi: 10.1126/science.3499668. [DOI] [PubMed] [Google Scholar]
  14. Desmarais D., Filion M., Lapointe L., Royal A. Cell-specific transcription of the peripherin gene in neuronal cell lines involves a cis-acting element surrounding the TATA box. EMBO J. 1992 Aug;11(8):2971–2980. doi: 10.1002/j.1460-2075.1992.tb05367.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Deutsch P. J., Jameson J. L., Habener J. F. Cyclic AMP responsiveness of human gonadotropin-alpha gene transcription is directed by a repeated 18-base pair enhancer. Alpha-promoter receptivity to the enhancer confers cell-preferential expression. J Biol Chem. 1987 Sep 5;262(25):12169–12174. [PubMed] [Google Scholar]
  16. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Dvorák M., Urbánek P., Bartůnek P., Paces V., Vlach J., Pecenka V., Arnold L., Trávnicek M., Ríman J. Transcription of the chicken myb proto-oncogene starts within a CpG island. Nucleic Acids Res. 1989 Jul 25;17(14):5651–5664. doi: 10.1093/nar/17.14.5651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Eggena P., Barrett J. D. Regulation and functional consequences of angiotensinogen gene expression. J Hypertens. 1992 Nov;10(11):1307–1311. doi: 10.1097/00004872-199211000-00001. [DOI] [PubMed] [Google Scholar]
  19. Fukamizu A., Sugimura K., Takimoto E., Sugiyama F., Seo M. S., Takahashi S., Hatae T., Kajiwara N., Yagami K., Murakami K. Chimeric renin-angiotensin system demonstrates sustained increase in blood pressure of transgenic mice carrying both human renin and human angiotensinogen genes. J Biol Chem. 1993 Jun 5;268(16):11617–11621. [PubMed] [Google Scholar]
  20. Fukamizu A., Takahashi S., Seo M. S., Tada M., Tanimoto K., Uehara S., Murakami K. Structure and expression of the human angiotensinogen gene. Identification of a unique and highly active promoter. J Biol Chem. 1990 May 5;265(13):7576–7582. [PubMed] [Google Scholar]
  21. Fukamizu A., Tanimoto K., Uehara S., Seo M. S., Handa S., Sagara M., Takahashi S., Imai T., Murakami K. Regulation of human renin and angiotensinogen genes. Biomed Biochim Acta. 1991;50(4-6):659–663. [PubMed] [Google Scholar]
  22. Ganten D., Wagner J., Zeh K., Bader M., Michel J. B., Paul M., Zimmermann F., Ruf P., Hilgenfeldt U., Ganten U. Species specificity of renin kinetics in transgenic rats harboring the human renin and angiotensinogen genes. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7806–7810. doi: 10.1073/pnas.89.16.7806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Gorski K., Carneiro M., Schibler U. Tissue-specific in vitro transcription from the mouse albumin promoter. Cell. 1986 Dec 5;47(5):767–776. doi: 10.1016/0092-8674(86)90519-2. [DOI] [PubMed] [Google Scholar]
  24. Guo W., Chen M., Yen T. S., Ou J. H. Hepatocyte-specific expression of the hepatitis B virus core promoter depends on both positive and negative regulation. Mol Cell Biol. 1993 Jan;13(1):443–448. doi: 10.1128/mcb.13.1.443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hilbert P., Lindpaintner K., Beckmann J. S., Serikawa T., Soubrier F., Dubay C., Cartwright P., De Gouyon B., Julier C., Takahasi S. Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats. Nature. 1991 Oct 10;353(6344):521–529. doi: 10.1038/353521a0. [DOI] [PubMed] [Google Scholar]
  26. Hong-Brown L. Q., Deschepper C. F. Effects of thyroid hormones on angiotensinogen gene expression in rat liver, brain, and cultured cells. Endocrinology. 1992 Mar;130(3):1231–1237. doi: 10.1210/endo.130.3.1537289. [DOI] [PubMed] [Google Scholar]
  27. Horikoshi M., Hai T., Lin Y. S., Green M. R., Roeder R. G. Transcription factor ATF interacts with the TATA factor to facilitate establishment of a preinitiation complex. Cell. 1988 Sep 23;54(7):1033–1042. doi: 10.1016/0092-8674(88)90118-3. [DOI] [PubMed] [Google Scholar]
  28. Howard T., Balogh R., Overbeek P., Bernstein K. E. Sperm-specific expression of angiotensin-converting enzyme (ACE) is mediated by a 91-base-pair promoter containing a CRE-like element. Mol Cell Biol. 1993 Jan;13(1):18–27. doi: 10.1128/mcb.13.1.18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ishii S., Kadonaga J. T., Tjian R., Brady J. N., Merlino G. T., Pastan I. Binding of the Sp1 transcription factor by the human Harvey ras1 proto-oncogene promoter. Science. 1986 Jun 13;232(4756):1410–1413. doi: 10.1126/science.3012774. [DOI] [PubMed] [Google Scholar]
  30. Jackson C. L., Schwartz S. M. Pharmacology of smooth muscle cell replication. Hypertension. 1992 Dec;20(6):713–736. doi: 10.1161/01.hyp.20.6.713. [DOI] [PubMed] [Google Scholar]
  31. Jacob H. J., Lindpaintner K., Lincoln S. E., Kusumi K., Bunker R. K., Mao Y. P., Ganten D., Dzau V. J., Lander E. S. Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell. 1991 Oct 4;67(1):213–224. doi: 10.1016/0092-8674(91)90584-l. [DOI] [PubMed] [Google Scholar]
  32. Jeunemaitre X., Soubrier F., Kotelevtsev Y. V., Lifton R. P., Williams C. S., Charru A., Hunt S. C., Hopkins P. N., Williams R. R., Lalouel J. M. Molecular basis of human hypertension: role of angiotensinogen. Cell. 1992 Oct 2;71(1):169–180. doi: 10.1016/0092-8674(92)90275-h. [DOI] [PubMed] [Google Scholar]
  33. Johnson P. F., Landschulz W. H., Graves B. J., McKnight S. L. Identification of a rat liver nuclear protein that binds to the enhancer core element of three animal viruses. Genes Dev. 1987 Apr;1(2):133–146. doi: 10.1101/gad.1.2.133. [DOI] [PubMed] [Google Scholar]
  34. Kalinyak J. E., Perlman A. J. Tissue-specific regulation of angiotensinogen mRNA accumulation by dexamethasone. J Biol Chem. 1987 Jan 5;262(1):460–464. [PubMed] [Google Scholar]
  35. Kimura S., Mullins J. J., Bunnemann B., Metzger R., Hilgenfeldt U., Zimmermann F., Jacob H., Fuxe K., Ganten D., Kaling M. High blood pressure in transgenic mice carrying the rat angiotensinogen gene. EMBO J. 1992 Mar;11(3):821–827. doi: 10.1002/j.1460-2075.1992.tb05119.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Klett C., Ganten D., Hellmann W., Kaling M., Ryffel G. U., Weimar-Ehl T., Hackenthal E. Regulation of hepatic angiotensinogen synthesis and secretion by steroid hormones. Endocrinology. 1992 Jun;130(6):3660–3668. doi: 10.1210/endo.130.6.1597163. [DOI] [PubMed] [Google Scholar]
  37. Klett C., Hellmann W., Müller F., Suzuki F., Nakanishi S., Ohkubo H., Ganten D., Hackenthal E. Angiotensin II controls angiotensinogen secretion at a pretranslational level. J Hypertens Suppl. 1988 Dec;6(4):S442–S445. doi: 10.1097/00004872-198812040-00139. [DOI] [PubMed] [Google Scholar]
  38. Klett C., Hellmann W., Suzuki F., Nakanishi S., Ohkubo H., Ganten D., Hackenthal E. Induction of angiotensinogen mRNA in hepatocytes by angiotensin II and glucocorticoids. Clin Exp Hypertens A. 1988;10(6):1009–1022. doi: 10.1080/07300077.1988.11878797. [DOI] [PubMed] [Google Scholar]
  39. Knowles B. B., Howe C. C., Aden D. P. Human hepatocellular carcinoma cell lines secrete the major plasma proteins and hepatitis B surface antigen. Science. 1980 Jul 25;209(4455):497–499. doi: 10.1126/science.6248960. [DOI] [PubMed] [Google Scholar]
  40. Kuipers O. P., Boot H. J., de Vos W. M. Improved site-directed mutagenesis method using PCR. Nucleic Acids Res. 1991 Aug 25;19(16):4558–4558. doi: 10.1093/nar/19.16.4558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Lifton R. P., Dluhy R. G., Powers M., Rich G. M., Cook S., Ulick S., Lalouel J. M. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature. 1992 Jan 16;355(6357):262–265. doi: 10.1038/355262a0. [DOI] [PubMed] [Google Scholar]
  42. Lowings P., Yavuzer U., Goding C. R. Positive and negative elements regulate a melanocyte-specific promoter. Mol Cell Biol. 1992 Aug;12(8):3653–3662. doi: 10.1128/mcb.12.8.3653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Lynch K. R., Peach M. J. Molecular biology of angiotensinogen. Hypertension. 1991 Mar;17(3):263–269. doi: 10.1161/01.hyp.17.3.263. [DOI] [PubMed] [Google Scholar]
  44. Maxam A. M., Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65(1):499–560. doi: 10.1016/s0076-6879(80)65059-9. [DOI] [PubMed] [Google Scholar]
  45. McCormick A., Brady H., Fukushima J., Karin M. The pituitary-specific regulatory gene GHF1 contains a minimal cell type-specific promoter centered around its TATA box. Genes Dev. 1991 Aug;5(8):1490–1503. doi: 10.1101/gad.5.8.1490. [DOI] [PubMed] [Google Scholar]
  46. Mullins J. J., Peters J., Ganten D. Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene. Nature. 1990 Apr 5;344(6266):541–544. doi: 10.1038/344541a0. [DOI] [PubMed] [Google Scholar]
  47. Ménard J., el Amrani A. I., Savoie F., Bouhnik J. Angiotensinogen: an attractive and underrated participant in hypertension and inflammation. Hypertension. 1991 Nov;18(5):705–707. doi: 10.1161/01.hyp.18.5.705. [DOI] [PubMed] [Google Scholar]
  48. Nakajima N., Horikoshi M., Roeder R. G. Factors involved in specific transcription by mammalian RNA polymerase II: purification, genetic specificity, and TATA box-promoter interactions of TFIID. Mol Cell Biol. 1988 Oct;8(10):4028–4040. doi: 10.1128/mcb.8.10.4028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Nakatani Y., Horikoshi M., Brenner M., Yamamoto T., Besnard F., Roeder R. G., Freese E. A downstream initiation element required for efficient TATA box binding and in vitro function of TFIID. Nature. 1990 Nov 1;348(6296):86–88. doi: 10.1038/348086a0. [DOI] [PubMed] [Google Scholar]
  50. Nishimura M., Milsted A., Block C. H., Brosnihan K. B., Ferrario C. M. Tissue renin-angiotensin systems in renal hypertension. Hypertension. 1992 Aug;20(2):158–167. doi: 10.1161/01.hyp.20.2.158. [DOI] [PubMed] [Google Scholar]
  51. Ohkubo H., Kawakami H., Kakehi Y., Takumi T., Arai H., Yokota Y., Iwai M., Tanabe Y., Masu M., Hata J. Generation of transgenic mice with elevated blood pressure by introduction of the rat renin and angiotensinogen genes. Proc Natl Acad Sci U S A. 1990 Jul;87(13):5153–5157. doi: 10.1073/pnas.87.13.5153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Pascoe L., Curnow K. M., Slutsker L., Connell J. M., Speiser P. W., New M. I., White P. C. Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2. Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8327–8331. doi: 10.1073/pnas.89.17.8327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Pugh B. F., Tjian R. Diverse transcriptional functions of the multisubunit eukaryotic TFIID complex. J Biol Chem. 1992 Jan 15;267(2):679–682. [PubMed] [Google Scholar]
  54. Rakugi H., Jacob H. J., Krieger J. E., Ingelfinger J. R., Pratt R. E. Vascular injury induces angiotensinogen gene expression in the media and neointima. Circulation. 1993 Jan;87(1):283–290. doi: 10.1161/01.cir.87.1.283. [DOI] [PubMed] [Google Scholar]
  55. Riegel A. T., Remenick J., Wolford R. G., Berard D. S., Hager G. L. A novel transcriptional activator (PO-B) binds between the TATA box and cap site of the pro-opiomelanocortin gene. Nucleic Acids Res. 1990 Aug 11;18(15):4513–4521. doi: 10.1093/nar/18.15.4513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Rigby P. W. Three in one and one in three: it all depends on TBP. Cell. 1993 Jan 15;72(1):7–10. doi: 10.1016/0092-8674(93)90042-o. [DOI] [PubMed] [Google Scholar]
  57. Ron D., Brasier A. R., Habener J. F. Transcriptional regulation of hepatic angiotensinogen gene expression by the acute-phase response. Mol Cell Endocrinol. 1990 Dec 21;74(3):C97–104. doi: 10.1016/0303-7207(90)90221-s. [DOI] [PubMed] [Google Scholar]
  58. Ron D., Brasier A. R., Wright K. A., Habener J. F. The permissive role of glucocorticoids on interleukin-1 stimulation of angiotensinogen gene transcription is mediated by an interaction between inducible enhancers. Mol Cell Biol. 1990 Aug;10(8):4389–4395. doi: 10.1128/mcb.10.8.4389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Schunkert H., Ingelfinger J. R., Hirsch A. T., Tang S. S., Litwin S. E., Talsness C. E., Dzau V. J. Evidence for tissue-specific activation of renal angiotensinogen mRNA expression in chronic stable experimental heart failure. J Clin Invest. 1992 Oct;90(4):1523–1529. doi: 10.1172/JCI116020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Sigmund C. D., Okuyama K., Ingelfinger J., Jones C. A., Mullins J. J., Kane C., Kim U., Wu C. Z., Kenny L., Rustum Y. Isolation and characterization of renin-expressing cell lines from transgenic mice containing a renin-promoter viral oncogene fusion construct. J Biol Chem. 1990 Nov 15;265(32):19916–19922. [PubMed] [Google Scholar]
  61. Smale S. T., Baltimore D. The "initiator" as a transcription control element. Cell. 1989 Apr 7;57(1):103–113. doi: 10.1016/0092-8674(89)90176-1. [DOI] [PubMed] [Google Scholar]
  62. Swick A. G., Blake M. C., Kahn J. W., Azizkhan J. C. Functional analysis of GC element binding and transcription in the hamster dihydrofolate reductase gene promoter. Nucleic Acids Res. 1989 Nov 25;17(22):9291–9304. doi: 10.1093/nar/17.22.9291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Takahashi S., Fukamizu A., Hasegawa T., Yokoyama M., Nomura T., Katsuki M., Murakami K. Expression of the human angiotensinogen gene in transgenic mice and transfected cells. Biochem Biophys Res Commun. 1991 Oct 31;180(2):1103–1109. doi: 10.1016/s0006-291x(05)81180-5. [DOI] [PubMed] [Google Scholar]
  64. Tamura K., Tanimoto K., Ishii M., Murakami K., Fukamizu A. Proximal and core DNA elements are required for efficient angiotensinogen promoter activation during adipogenic differentiation. J Biol Chem. 1993 Jul 15;268(20):15024–15032. [PubMed] [Google Scholar]
  65. Tamura K., Tanimoto K., Murakami K., Fukamizu A. A combination of upstream and proximal elements is required for efficient expression of the mouse renin promoter in cultured cells. Nucleic Acids Res. 1992 Jul 25;20(14):3617–3623. doi: 10.1093/nar/20.14.3617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Tamura K., Tanimoto K., Murakami K., Fukamizu A. Activation of mouse renin promoter by cAMP and c-Jun in a kidney-derived cell line. Biochim Biophys Acta. 1993 Mar 20;1172(3):306–310. doi: 10.1016/0167-4781(93)90218-3. [DOI] [PubMed] [Google Scholar]
  67. Tamura K., Tanimoto K., Takahashi S., Sagara M., Fukamizu A., Murakami K. Structure and expression of the mouse angiotensinogen gene. Jpn Heart J. 1992 Jan;33(1):113–124. doi: 10.1536/ihj.33.113. [DOI] [PubMed] [Google Scholar]
  68. Ward K., Hata A., Jeunemaitre X., Helin C., Nelson L., Namikawa C., Farrington P. F., Ogasawara M., Suzumori K., Tomoda S. A molecular variant of angiotensinogen associated with preeclampsia. Nat Genet. 1993 May;4(1):59–61. doi: 10.1038/ng0593-59. [DOI] [PubMed] [Google Scholar]
  69. Watt G. C., Harrap S. B., Foy C. J., Holton D. W., Edwards H. V., Davidson H. R., Connor J. M., Lever A. F., Fraser R. Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: a four-corners approach to the identification of genetic determinants of blood pressure. J Hypertens. 1992 May;10(5):473–482. doi: 10.1097/00004872-199205000-00011. [DOI] [PubMed] [Google Scholar]
  70. Wefald F. C., Devlin B. H., Williams R. S. Functional heterogeneity of mammalian TATA-box sequences revealed by interaction with a cell-specific enhancer. Nature. 1990 Mar 15;344(6263):260–262. doi: 10.1038/344260a0. [DOI] [PubMed] [Google Scholar]
  71. Zee R. Y., Lou Y. K., Griffiths L. R., Morris B. J. Association of a polymorphism of the angiotensin I-converting enzyme gene with essential hypertension. Biochem Biophys Res Commun. 1992 Apr 15;184(1):9–15. doi: 10.1016/0006-291x(92)91150-o. [DOI] [PubMed] [Google Scholar]

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