Search tips
Search criteria 


Logo of narLink to Publisher's site
Nucleic Acids Res. 1987 May 11; 15(9): 3801–3821.
PMCID: PMC340783

Dual tissue-specific expression of apo-AII is directed by an upstream enhancer.


Apolipoprotein-AII (apo-AII) is one of a family of evolutionarily related proteins which play a crucial role in lipid transport and metabolism. The serum levels of human apo-AII have been shown to be inversely correlated to the incidence of coronary heart disease and its expression to be limited to the liver and intestine. Here we demonstrate that this dual tissue-specificity involves DNA sequences located in a 259 bp region centred 782 bp upstream from the transcription initiation site. These sequences function in an orientation-independent manner and are absolutely required for transcription from the apo-AII promoter. The regulatory region contains sequences which are homologous to the apo-AI, beta-globin and immunoglobulin gene promoters and to the immunoglobulin heavy-chain enhancer.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.4M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Edlund T, Walker MD, Barr PJ, Rutter WJ. Cell-specific expression of the rat insulin gene: evidence for role of two distinct 5' flanking elements. Science. 1985 Nov 22;230(4728):912–916. [PubMed]
  • Foster J, Stafford J, Queen C. An immunoglobulin promoter displays cell-type specificity independently of the enhancer. Nature. 315(6018):423–425. [PubMed]
  • Stout JT, Chen HY, Brennand J, Caskey CT, Brinster RL. Expression of human HPRT in the central nervous system of transgenic mice. Nature. 1985 Sep 19;317(6034):250–252. [PubMed]
  • Theisen M, Stief A, Sippel AE. The lysozyme enhancer: cell-specific activation of the chicken lysozyme gene by a far-upstream DNA element. EMBO J. 1986 Apr;5(4):719–724. [PubMed]
  • Wright S, Rosenthal A, Flavell R, Grosveld F. DNA sequences required for regulated expression of beta-globin genes in murine erythroleukemia cells. Cell. 1984 Aug;38(1):265–273. [PubMed]
  • Walker MD, Edlund T, Boulet AM, Rutter WJ. Cell-specific expression controlled by the 5'-flanking region of insulin and chymotrypsin genes. Nature. 1983 Dec 8;306(5943):557–561. [PubMed]
  • Gillies SD, Folsom V, Tonegawa S. Cell type-specific enhancer element associated with a mouse MHC gene, E beta. Nature. 1984 Aug 16;310(5978):594–597. [PubMed]
  • Prochownik EV. Relationship between an enhancer element in the human antithrombin III gene and an immunoglobulin light-chain gene enhancer. Nature. 316(6031):845–848. [PubMed]
  • Ciliberto G, Dente L, Cortese R. Cell-specific expression of a transfected human alpha 1-antitrypsin gene. Cell. 1985 Jun;41(2):531–540. [PubMed]
  • Basu SK, Ho YK, Brown MS, Bilheimer DW, Anderson RG, Goldstein JL. Biochemical and genetic studies of the apoprotein E secreted by mouse macrophages and human monocytes. J Biol Chem. 1982 Aug 25;257(16):9788–9795. [PubMed]
  • Zannis VI, Kurnit DM, Breslow JL. Hepatic apo-A-I and apo-E and intestinal apo-A-I are synthesized in precursor isoprotein forms by organ cultures of human fetal tissues. J Biol Chem. 1982 Jan 10;257(1):536–544. [PubMed]
  • Zannis VI, Cole FS, Jackson CL, Kurnit DM, Karathanasis SK. Distribution of apolipoprotein A-I, C-II, C-III, and E mRNA in fetal human tissues. Time-dependent induction of apolipoprotein E mRNA by cultures of human monocyte-macrophages. Biochemistry. 1985 Jul 30;24(16):4450–4455. [PubMed]
  • Blue ML, Williams DL, Zucker S, Khan SA, Blum CB. Apolipoprotein E synthesis in human kidney, adrenal gland, and liver. Proc Natl Acad Sci U S A. 1983 Jan;80(1):283–287. [PubMed]
  • Stein Y, Glangeaud MC, Fainaru M, Stein O. The removal of cholesterol from aortic smooth muscle cells in culture and Landschutz ascites cells by fractions of human high-density apolipoprotein. Biochim Biophys Acta. 1975 Jan 24;380(1):106–118. [PubMed]
  • Rhoads GG, Gulbrandsen CL, Kagan A. Serum lipoproteins and coronary heart disease in a population study of Hawaii Japanese men. N Engl J Med. 1976 Feb 5;294(6):293–298. [PubMed]
  • Castelli WP, Doyle JT, Gordon T, Hames CG, Hjortland MC, Hulley SB, Kagan A, Zukel WJ. Alcohol and blood lipids. The cooperative lipoprotein phenotyping study. Lancet. 1977 Jul 23;2(8030):153–155. [PubMed]
  • Miller NE, Weinstein DB, Carew TE, Koschinsky T, Steinberg D. Interaction between high density and low density lipoproteins uptake and degradation by cultured human fibroblasts. J Clin Invest. 1977 Jul;60(1):78–88. [PMC free article] [PubMed]
  • Albers JJ, Cheung MC, Hazzard WR. High-density lipoproteins in myocardial infarction survivors. Metabolism. 1978 Apr;27(4):479–485. [PubMed]
  • Willett W, Hennekens CH, Siegel AJ, Adner MM, Castelli WP. Alcohol consumption and high density lipoprotein cholesterol in marathon runners. N Engl J Med. 1980 Nov 13;303(20):1159–1161. [PubMed]
  • Rees A, Shoulders CC, Stocks J, Galton DJ, Baralle FE. DNA polymorphism adjacent to human apoprotein A-1 gene: relation to hypertriglyceridaemia. Lancet. 1983 Feb 26;1(8322):444–446. [PubMed]
  • Rees A, Stocks J, Sharpe CR, Vella MA, Shoulders CC, Katz J, Jowett NI, Baralle FE, Galton DJ. Deoxyribonucleic acid polymorphism in the apolipoprotein A-1-C-III gene cluster. Association with hypertriglyceridemia. J Clin Invest. 1985 Sep;76(3):1090–1095. [PMC free article] [PubMed]
  • Knott TJ, Eddy RL, Robertson ME, Priestley LM, Scott J, Shows TB. Chromosomal localization of the human apoprotein CI gene and of a polymorphic apoprotein AII gene. Biochem Biophys Res Commun. 1984 Nov 30;125(1):299–306. [PubMed]
  • Scott J, Knott TJ, Priestley LM, Robertson ME, Mann DV, Kostner G, Miller GJ, Miller NE. High-density lipoprotein composition is altered by a common DNA polymorphism adjacent to apoprotein AII gene in man. Lancet. 1985 Apr 6;1(8432):771–773. [PubMed]
  • Rachmilewitz D, Albers JJ, Saunders DR, Fainaru M. Apoprotein synthesis by human duodenojejunal mucosa. Gastroenterology. 1978 Oct;75(4):677–682. [PubMed]
  • Anderson DW, Schaefer EJ, Bronzert TJ, Lindgren FT, Forte T, Starzl TE, Niblack GD, Zech LA, Brewer HB., Jr Transport of apolipoproteins A-I and A-II by human thoracic duct lymph. J Clin Invest. 1981 Mar;67(3):857–866. [PMC free article] [PubMed]
  • Bisgaier CL, Glickman RM. Intestinal synthesis, secretion, and transport of lipoproteins. Annu Rev Physiol. 1983;45:625–636. [PubMed]
  • Gordon JI, Budelier KA, Sims HF, Edelstein C, Scanu AM, Strauss AW. Biosynthesis of human preproapolipoprotein A-II. J Biol Chem. 1983 Nov 25;258(22):14054–14059. [PubMed]
  • Shelley CS, Sharpe CR, Baralle FE, Shoulders CC. Comparison of the human apolipoprotein genes. Apo AII presents a unique functional intron-exon junction. J Mol Biol. 1985 Nov 5;186(1):43–51. [PubMed]
  • Mellon P, Parker V, Gluzman Y, Maniatis T. Identification of DNA sequences required for transcription of the human alpha 1-globin gene in a new SV40 host-vector system. Cell. 1981 Dec;27(2 Pt 1):279–288. [PubMed]
  • Maxam AM, Gilbert W. A new method for sequencing DNA. Proc Natl Acad Sci U S A. 1977 Feb;74(2):560–564. [PubMed]
  • Maxam AM, Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65(1):499–560. [PubMed]
  • Aden DP, Fogel A, Plotkin S, Damjanov I, Knowles BB. Controlled synthesis of HBsAg in a differentiated human liver carcinoma-derived cell line. Nature. 1979 Dec 6;282(5739):615–616. [PubMed]
  • Knowles BB, Howe CC, Aden DP. Human hepatocellular carcinoma cell lines secrete the major plasma proteins and hepatitis B surface antigen. Science. 1980 Jul 25;209(4455):497–499. [PubMed]
  • Zannis VI, Breslow JL, SanGiacomo TR, Aden DP, Knowles BB. Characterization of the major apolipoproteins secreted by two human hepatoma cell lines. Biochemistry. 1981 Dec 8;20(25):7089–7096. [PubMed]
  • Fair DS, Bahnak BR. Human hepatoma cells secrete single chain factor X, prothrombin, and antithrombin III. Blood. 1984 Jul;64(1):194–204. [PubMed]
  • Marshall CJ, Franks LM, Carbonell AW. Markers of neoplastic transformation in epithelial cell lines derived from human carcinomas. J Natl Cancer Inst. 1977 Jun;58(6):1743–1751. [PubMed]
  • O'Toole CM, Povey S, Hepburn P, Franks LM. Identity of some human bladder cancer cell lines. Nature. 1983 Feb 3;301(5899):429–430. [PubMed]
  • Rousset M, Chevalier G, Rousset JP, Dussaulx E, Zweibaum A. Presence and cell growth-related variations of glycogen in human colorectal adenocarcinoma cell lines in culture. Cancer Res. 1979 Feb;39(2 Pt 1):531–534. [PubMed]
  • Rousset M, Laburthe M, Pinto M, Chevalier G, Rouyer-Fessard C, Dussaulx E, Trugnan G, Boige N, Brun JL, Zweibaum A. Enterocytic differentiation and glucose utilization in the human colon tumor cell line Caco-2: modulation by forskolin. J Cell Physiol. 1985 Jun;123(3):377–385. [PubMed]
  • Grasset E, Pinto M, Dussaulx E, Zweibaum A, Desjeux JF. Epithelial properties of human colonic carcinoma cell line Caco-2: electrical parameters. Am J Physiol. 1984 Sep;247(3 Pt 1):C260–C267. [PubMed]
  • Graham FL, van der Eb AJ. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. [PubMed]
  • Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. [PubMed]
  • Glisin V, Crkvenjakov R, Byus C. Ribonucleic acid isolated by cesium chloride centrifugation. Biochemistry. 1974 Jun 4;13(12):2633–2637. [PubMed]
  • Kaplan BB, Bernstein SL, Gioio AE. An improved method for the rapid isolation of brain ribonucleic acid. Biochem J. 1979 Oct 1;183(1):181–184. [PubMed]
  • Grosveld GC, de Boer E, Shewmaker CK, Flavell RA. DNA sequences necessary for transcription of the rabbit beta-globin gene in vivo. Nature. 1982 Jan 14;295(5845):120–126. [PubMed]
  • Banerji J, Rusconi S, Schaffner W. Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences. Cell. 1981 Dec;27(2 Pt 1):299–308. [PubMed]
  • Moreau P, Hen R, Wasylyk B, Everett R, Gaub MP, Chambon P. The SV40 72 base repair repeat has a striking effect on gene expression both in SV40 and other chimeric recombinants. Nucleic Acids Res. 1981 Nov 25;9(22):6047–6068. [PMC free article] [PubMed]
  • Khoury G, Gruss P. Enhancer elements. Cell. 1983 Jun;33(2):313–314. [PubMed]
  • Chambon P, Dierich A, Gaub MP, Jakowlev S, Jongstra J, Krust A, LePennec JP, Oudet P, Reudelhuber T. Promoter elements of genes coding for proteins and modulation of transcription by estrogens and progesterone. Recent Prog Horm Res. 1984;40:1–42. [PubMed]
  • Garabedian MJ, Hung MC, Wensink PC. Independent control elements that determine yolk protein gene expression in alternative Drosophila tissues. Proc Natl Acad Sci U S A. 1985 Mar;82(5):1396–1400. [PubMed]
  • Garabedian MJ, Shepherd BM, Wensink PC. A tissue-specific transcription enhancer from the Drosophila yolk protein 1 gene. Cell. 1986 Jun 20;45(6):859–867. [PubMed]
  • Gopal TV, Shimada T, Baur AW, Nienhuis AW. Contribution of promoter to tissue-specific expression of the mouse immunoglobulin kappa gene. Science. 1985 Sep 13;229(4718):1102–1104. [PubMed]
  • Grosschedl R, Baltimore D. Cell-type specificity of immunoglobulin gene expression is regulated by at least three DNA sequence elements. Cell. 1985 Jul;41(3):885–897. [PubMed]
  • Mason JO, Williams GT, Neuberger MS. Transcription cell type specificity is conferred by an immunoglobulin VH gene promoter that includes a functional consensus sequence. Cell. 1985 Jun;41(2):479–487. [PubMed]
  • Picard D, Schaffner W. Cell-type preference of immunoglobulin kappa and lambda gene promoters. EMBO J. 1985 Nov;4(11):2831–2838. [PubMed]
  • Okazaki K, Yasuda K, Kondoh H, Okada TS. DNA sequences responsible for tissue-specific expression of a chicken alpha-crystallin gene in mouse lens cells. EMBO J. 1985 Oct;4(10):2589–2595. [PubMed]
  • Church GM, Ephrussi A, Gilbert W, Tonegawa S. Cell-type-specific contacts to immunoglobulin enhancers in nuclei. Nature. 313(6005):798–801. [PubMed]
  • Ephrussi A, Church GM, Tonegawa S, Gilbert W. B lineage--specific interactions of an immunoglobulin enhancer with cellular factors in vivo. Science. 1985 Jan 11;227(4683):134–140. [PubMed]
  • Mangin M, Ares M, Jr, Weiner AM. Human U2 small nuclear RNA genes contain an upstream enhancer. EMBO J. 1986 May;5(5):987–995. [PubMed]
  • Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell. 1986 Aug 29;46(5):705–716. [PubMed]
  • Parslow TG, Blair DL, Murphy WJ, Granner DK. Structure of the 5' ends of immunoglobulin genes: a novel conserved sequence. Proc Natl Acad Sci U S A. 1984 May;81(9):2650–2654. [PubMed]
  • Falkner FG, Zachau HG. Correct transcription of an immunoglobulin kappa gene requires an upstream fragment containing conserved sequence elements. Nature. 1984 Jul 5;310(5972):71–74. [PubMed]
  • Mercola M, Goverman J, Mirell C, Calame K. Immunoglobulin heavy-chain enhancer requires one or more tissue-specific factors. Science. 1985 Jan 18;227(4684):266–270. [PubMed]
  • Hromas R, Van Ness B. Nuclear factors bind to regulatory regions of the mouse kappa immunoglobulin gene. Nucleic Acids Res. 1986 Jun 25;14(12):4837–4848. [PMC free article] [PubMed]
  • Singh H, Sen R, Baltimore D, Sharp PA. A nuclear factor that binds to a conserved sequence motif in transcriptional control elements of immunoglobulin genes. Nature. 1986 Jan 9;319(6049):154–158. [PubMed]
  • Weinberger J, Baltimore D, Sharp PA. Distinct factors bind to apparently homologous sequences in the immunoglobulin heavy-chain enhancer. Nature. 322(6082):846–848. [PubMed]
  • Lusky M, Berg L, Weiher H, Botchan M. Bovine papilloma virus contains an activator of gene expression at the distal end of the early transcription unit. Mol Cell Biol. 1983 Jun;3(6):1108–1122. [PMC free article] [PubMed]
  • Ohlsson H, Edlund T. Sequence-specific interactions of nuclear factors with the insulin gene enhancer. Cell. 1986 Apr 11;45(1):35–44. [PubMed]
  • Orkin SH, Kazazian HH, Jr, Antonarakis SE, Goff SC, Boehm CD, Sexton JP, Waber PG, Giardina PJ. Linkage of beta-thalassaemia mutations and beta-globin gene polymorphisms with DNA polymorphisms in human beta-globin gene cluster. Nature. 1982 Apr 15;296(5858):627–631. [PubMed]
  • Treisman R, Orkin SH, Maniatis T. Specific transcription and RNA splicing defects in five cloned beta-thalassaemia genes. Nature. 1983 Apr 14;302(5909):591–596. [PubMed]
  • Barker WC, Dayhoff MO. Evolution of lipoproteins deduced from protein sequence data. Comp Biochem Physiol B. 1977;57(4):309–315. [PubMed]
  • Boguski MS, Birkenmeier EH, Elshourbagy NA, Taylor JM, Gordon JI. Evolution of the apolipoproteins. Structure of the rat apo-A-IV gene and its relationship to the human genes for apo-A-I, C-III, and E. J Biol Chem. 1986 May 15;261(14):6398–6407. [PubMed]
  • Wei CF, Tsao YK, Robberson DL, Gotto AM, Jr, Brown K, Chan L. The structure of the human apolipoprotein C-II gene. Electron microscopic analysis of RNA:DNA hybrids, complete nucleotide sequence, and identification of 5' homologous sequences among apolipoprotein genes. J Biol Chem. 1985 Dec 5;260(28):15211–15221. [PubMed]
  • Weiher H, König M, Gruss P. Multiple point mutations affecting the simian virus 40 enhancer. Science. 1983 Feb 11;219(4585):626–631. [PubMed]
  • Fager G, Wiklund O, Olofsson SO, Wilhelmsen L, Bondjers G. Multivariate analyses of serum apolipoproteins and risk factors in relation to acute myocardial infarction. Arteriosclerosis. 1981 Jul-Aug;1(4):273–279. [PubMed]
  • Pilger E, Pristautz H, Pfeiffer KP, Kostner G. Risk factors for peripheral atherosclerosis. Retrospective evaluation by stepwise discriminant analysis. Arteriosclerosis. 1983 Jan-Feb;3(1):57–63. [PubMed]
  • Rall SC, Jr, Weisgraber KH, Innerarity TL, Mahley RW. Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects. Proc Natl Acad Sci U S A. 1982 Aug;79(15):4696–4700. [PubMed]
  • Karathanasis SK, Norum RA, Zannis VI, Breslow JL. An inherited polymorphism in the human apolipoprotein A-I gene locus related to the development of atherosclerosis. Nature. 1983 Feb 24;301(5902):718–720. [PubMed]
  • Karathanasis SK, Zannis VI, Breslow JL. A DNA insertion in the apolipoprotein A-I gene of patients with premature atherosclerosis. Nature. 305(5937):823–825. [PubMed]
  • Ordovas JM, Schaefer EJ, Salem D, Ward RH, Glueck CJ, Vergani C, Wilson PW, Karathanasis SK. Apolipoprotein A-I gene polymorphism associated with premature coronary artery disease and familial hypoalphalipoproteinemia. N Engl J Med. 1986 Mar 13;314(11):671–677. [PubMed]
  • Lusis AJ, LeBoeuf RC. Genetic control of plasma lipid transport: mouse model. Methods Enzymol. 1986;128:877–894. [PubMed]
  • Lawn RM, Efstratiadis A, O'Connell C, Maniatis T. The nucleotide sequence of the human beta-globin gene. Cell. 1980 Oct;21(3):647–651. [PubMed]
  • McConkey EH, Hopkins JW. Molecular weights of some HeLa ribosomal RNA's. J Mol Biol. 1969 Feb 14;39(3):545–550. [PubMed]
  • Dierks P, van Ooyen A, Cochran MD, Dobkin C, Reiser J, Weissmann C. Three regions upstream from the cap site are required for efficient and accurate transcription of the rabbit beta-globin gene in mouse 3T6 cells. Cell. 1983 Mar;32(3):695–706. [PubMed]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press