Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1993 Feb 15;90(4):1369–1373. doi: 10.1073/pnas.90.4.1369

5' control regions of the apolipoprotein(a) gene and members of the related plasminogen gene family.

D P Wade 1, J G Clarke 1, G E Lindahl 1, A C Liu 1, B R Zysow 1, K Meer 1, K Schwartz 1, R M Lawn 1
PMCID: PMC45874  PMID: 7679504

Abstract

Elevated blood levels of apolipoprotein(a), the component of lipoprotein(a) that distinguishes it from low density lipoprotein, are a major risk factor for atherosclerosis. The apolipoprotein(a) gene is highly similar to the plasminogen gene and to at least four other genes or pseudogenes. The 5' untranslated and flanking sequences of these six genes contain extensive regions of near identity and share sequence elements involved in the initiation of transcription and translation. About 1000 base pairs of flanking DNA of each gene are sufficient to promote transcription in cultured hepatocytes. The apolipoprotein(a) gene promoter contains functional interleukin 6-responsive elements, consistent with the reported acute-phase response of apolipoprotein(a). Flanking genomic fragments of the apoliprotein(a) gene from two individuals with vastly different plasma apolipoprotein(a) concentrations have sequence differences that are reflected in differences in the rate of in vitro transcription.

Full text

PDF
1369

Images in this article

1370Image
on p.1370
1371Image
on p.1371
1372Image
on p.1372

Selected References

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

  1. Akira S., Isshiki H., Sugita T., Tanabe O., Kinoshita S., Nishio Y., Nakajima T., Hirano T., Kishimoto T. A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. EMBO J. 1990 Jun;9(6):1897–1906. doi: 10.1002/j.1460-2075.1990.tb08316.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Azrolan N., Gavish D., Breslow J. L. Plasma lipoprotein(a) concentration is controlled by apolipoprotein(a) (apo(a)) protein size and the abundance of hepatic apo(a) mRNA in a cynomolgus monkey model. J Biol Chem. 1991 Jul 25;266(21):13866–13872. [PubMed] [Google Scholar]
  3. Boerwinkle E., Leffert C. C., Lin J., Lackner C., Chiesa G., Hobbs H. H. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations. J Clin Invest. 1992 Jul;90(1):52–60. doi: 10.1172/JCI115855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Castellino F. J., Beals J. M. The genetic relationships between the kringle domains of human plasminogen, prothrombin, tissue plasminogen activator, urokinase, and coagulation factor XII. J Mol Evol. 1987;26(4):358–369. doi: 10.1007/BF02101155. [DOI] [PubMed] [Google Scholar]
  5. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Drayna D. T., Hegele R. A., Hass P. E., Emi M., Wu L. L., Eaton D. L., Lawn R. M., Williams R. R., White R. L., Lalouel J. M. Genetic linkage between lipoprotein(a) phenotype and a DNA polymorphism in the plasminogen gene. Genomics. 1988 Oct;3(3):230–236. doi: 10.1016/0888-7543(88)90084-5. [DOI] [PubMed] [Google Scholar]
  8. Forsgren M., Råden B., Israelsson M., Larsson K., Hedén L. O. Molecular cloning and characterization of a full-length cDNA clone for human plasminogen. FEBS Lett. 1987 Mar 23;213(2):254–260. doi: 10.1016/0014-5793(87)81501-6. [DOI] [PubMed] [Google Scholar]
  9. Frank S. L., Klisak I., Sparkes R. S., Mohandas T., Tomlinson J. E., McLean J. W., Lawn R. M., Lusis A. J. The apolipoprotein(a) gene resides on human chromosome 6q26-27, in close proximity to the homologous gene for plasminogen. Hum Genet. 1988 Aug;79(4):352–356. doi: 10.1007/BF00282175. [DOI] [PubMed] [Google Scholar]
  10. Gavish D., Azrolan N., Breslow J. L. Plasma Ip(a) concentration is inversely correlated with the ratio of Kringle IV/Kringle V encoding domains in the apo(a) gene. J Clin Invest. 1989 Dec;84(6):2021–2027. doi: 10.1172/JCI114395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hardon E. M., Frain M., Paonessa G., Cortese R. Two distinct factors interact with the promoter regions of several liver-specific genes. EMBO J. 1988 Jun;7(6):1711–1719. doi: 10.1002/j.1460-2075.1988.tb03000.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hattori M., Abraham L. J., Northemann W., Fey G. H. Acute-phase reaction induces a specific complex between hepatic nuclear proteins and the interleukin 6 response element of the rat alpha 2-macroglobulin gene. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2364–2368. doi: 10.1073/pnas.87.6.2364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ichinose A. Multiple members of the plasminogen-apolipoprotein(a) gene family associated with thrombosis. Biochemistry. 1992 Mar 31;31(12):3113–3118. doi: 10.1021/bi00127a011. [DOI] [PubMed] [Google Scholar]
  14. Knight B. L., Perombelon Y. F., Soutar A. K., Wade D. P., Seed M. Catabolism of lipoprotein(a) in familial hypercholesterolaemic subjects. Atherosclerosis. 1991 Apr;87(2-3):227–237. doi: 10.1016/0021-9150(91)90025-x. [DOI] [PubMed] [Google Scholar]
  15. Koschinsky M. L., Beisiegel U., Henne-Bruns D., Eaton D. L., Lawn R. M. Apolipoprotein(a) size heterogeneity is related to variable number of repeat sequences in its mRNA. Biochemistry. 1990 Jan 23;29(3):640–644. doi: 10.1021/bi00455a007. [DOI] [PubMed] [Google Scholar]
  16. Krempler F., Kostner G. M., Bolzano K., Sandhofer F. Turnover of lipoprotein (a) in man. J Clin Invest. 1980 Jun;65(6):1483–1490. doi: 10.1172/JCI109813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lackner C., Boerwinkle E., Leffert C. C., Rahmig T., Hobbs H. H. Molecular basis of apolipoprotein (a) isoform size heterogeneity as revealed by pulsed-field gel electrophoresis. J Clin Invest. 1991 Jun;87(6):2153–2161. doi: 10.1172/JCI115248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Landschulz W. H., Johnson P. F., Adashi E. Y., Graves B. J., McKnight S. L. Isolation of a recombinant copy of the gene encoding C/EBP. Genes Dev. 1988 Jul;2(7):786–800. doi: 10.1101/gad.2.7.786. [DOI] [PubMed] [Google Scholar]
  19. Laplaud P. M., Beaubatie L., Rall S. C., Jr, Luc G., Saboureau M. Lipoprotein[a] is the major apoB-containing lipoprotein in the plasma of a hibernator, the hedgehog (Erinaceus europaeus). J Lipid Res. 1988 Sep;29(9):1157–1170. [PubMed] [Google Scholar]
  20. Maeda S., Abe A., Seishima M., Makino K., Noma A., Kawade M. Transient changes of serum lipoprotein(a) as an acute phase protein. Atherosclerosis. 1989 Aug;78(2-3):145–150. doi: 10.1016/0021-9150(89)90218-9. [DOI] [PubMed] [Google Scholar]
  21. Malgaretti N., Bruno L., Pontoglio M., Candiani G., Meroni G., Ottolenghi S., Taramelli R. Definition of the transcription initiation site of human plasminogen gene in liver and non hepatic cell lines. Biochem Biophys Res Commun. 1990 Dec 31;173(3):1013–1018. doi: 10.1016/s0006-291x(05)80887-3. [DOI] [PubMed] [Google Scholar]
  22. Malinowski D. P., Sadler J. E., Davie E. W. Characterization of a complementary deoxyribonucleic acid coding for human and bovine plasminogen. Biochemistry. 1984 Aug 28;23(18):4243–4250. doi: 10.1021/bi00313a035. [DOI] [PubMed] [Google Scholar]
  23. McLean J. W., Tomlinson J. E., Kuang W. J., Eaton D. L., Chen E. Y., Fless G. M., Scanu A. M., Lawn R. M. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature. 1987 Nov 12;330(6144):132–137. doi: 10.1038/330132a0. [DOI] [PubMed] [Google Scholar]
  24. Murray J. C., Buetow K. H., Donovan M., Hornung S., Motulsky A. G., Disteche C., Dyer K., Swisshelm K., Anderson J., Giblett E. Linkage disequilibrium of plasminogen polymorphisms and assignment of the gene to human chromosome 6q26-6q27. Am J Hum Genet. 1987 Apr;40(4):338–350. [PMC free article] [PubMed] [Google Scholar]
  25. Patthy L. Evolution of the proteases of blood coagulation and fibrinolysis by assembly from modules. Cell. 1985 Jul;41(3):657–663. doi: 10.1016/s0092-8674(85)80046-5. [DOI] [PubMed] [Google Scholar]
  26. Rhoads G. G., Dahlen G., Berg K., Morton N. E., Dannenberg A. L. Lp(a) lipoprotein as a risk factor for myocardial infarction. JAMA. 1986 Nov 14;256(18):2540–2544. [PubMed] [Google Scholar]
  27. Rosengren A., Wilhelmsen L., Eriksson E., Risberg B., Wedel H. Lipoprotein (a) and coronary heart disease: a prospective case-control study in a general population sample of middle aged men. BMJ. 1990 Dec 1;301(6763):1248–1251. doi: 10.1136/bmj.301.6763.1248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sandholzer C., Saha N., Kark J. D., Rees A., Jaross W., Dieplinger H., Hoppichler F., Boerwinkle E., Utermann G. Apo(a) isoforms predict risk for coronary heart disease. A study in six populations. Arterioscler Thromb. 1992 Oct;12(10):1214–1226. doi: 10.1161/01.atv.12.10.1214. [DOI] [PubMed] [Google Scholar]
  29. Scanu A. M., Fless G. M. Lipoprotein (a). Heterogeneity and biological relevance. J Clin Invest. 1990 Jun;85(6):1709–1715. doi: 10.1172/JCI114625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Scanu A. M., Lawn R. M., Berg K. Lipoprotein(a) and atherosclerosis. Ann Intern Med. 1991 Aug 1;115(3):209–218. doi: 10.7326/0003-4819-115-3-209. [DOI] [PubMed] [Google Scholar]
  31. Utermann G., Kraft H. G., Menzel H. J., Hopferwieser T., Seitz C. Genetics of the quantitative Lp(a) lipoprotein trait. I. Relation of LP(a) glycoprotein phenotypes to Lp(a) lipoprotein concentrations in plasma. Hum Genet. 1988 Jan;78(1):41–46. doi: 10.1007/BF00291232. [DOI] [PubMed] [Google Scholar]
  32. Utermann G. The mysteries of lipoprotein(a). Science. 1989 Nov 17;246(4932):904–910. doi: 10.1126/science.2530631. [DOI] [PubMed] [Google Scholar]
  33. Wade D. P., Knight B. L., Harders-Spengel K., Soutar A. K. Detection and quantitation of apolipoprotein(a) mRNA in human liver and its relationship with plasma lipoprotein(a) concentration. Atherosclerosis. 1991 Nov;91(1-2):63–72. doi: 10.1016/0021-9150(91)90187-8. [DOI] [PubMed] [Google Scholar]
  34. Weissbach L., Treadwell B. V. A plasminogen-related gene is expressed in cancer cells. Biochem Biophys Res Commun. 1992 Jul 31;186(2):1108–1114. doi: 10.1016/0006-291x(92)90861-e. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES