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. 1993 Oct 15;295(Pt 2):379–386. doi: 10.1042/bj2950379

Cloning and tissue-specific expression of the gene for mouse C-reactive protein.

N O Ku 1, R F Mortensen 1
PMCID: PMC1134892  PMID: 7916620

Abstract

C-reactive protein is a serum acute-phase reactant that increases several thousand-fold in concentration during inflammation in most mammals. However, mouse C-reactive protein is considered to be a minor acute-phase reactant, since its blood level increases only from approx. 0.1 to 1-2 micrograms/ml. A mouse genomic clone of approximately 5 kb was obtained to determine the molecular basis for the regulation of the expression of mouse C-reactive protein. Several cis-acting elements in the 5' flanking region that potentially regulate transcription were identified: two glucocorticoid-responsive elements, two CCAAT-enhancer-binding protein C (C/EBP) consensus elements that are required for the interleukin-1 responsiveness of some acute-phase reactant genes, an interleukin-6-responsive element, two hepatocyte nuclear factor-1 (HNF-1) elements and a single heat-shock element. Transfection of the hepatoma cell line Hep 3B.2 with a pCAT expression vector containing the 5' flanking sequence from -1083 to -3 bp from the transcriptional start site, and truncations of this sequence, localized elements that control the tissue-specific expression of mouse C-reactive protein to the two HNF-1 elements and a C/EBP, interleukin-1-responsive element located between -220 and -153, and -90 and -50 bp from the transcriptional start site. A constitutive nuclear protein from mouse-liver hepatocytes specifically binds to the HNF-1 elements. These findings explain the tissue-specific expression of the gene, as well as its limited expression during the acute-phase response.

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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. Ballou S. P., Kushner I. C-reactive protein and the acute phase response. Adv Intern Med. 1992;37:313–336. [PubMed] [Google Scholar]
  3. Baltz M. L., de Beer F. C., Feinstein A., Munn E. A., Milstein C. P., Fletcher T. C., March J. F., Taylor J., Bruton C., Clamp J. R. Phylogenetic aspects of C-reactive protein and related proteins. Ann N Y Acad Sci. 1982;389:49–75. doi: 10.1111/j.1749-6632.1982.tb22125.x. [DOI] [PubMed] [Google Scholar]
  4. Baumann H., Jahreis G. P., Morella K. K. Interaction of cytokine- and glucocorticoid-response elements of acute-phase plasma protein genes. Importance of glucocorticoid receptor level and cell type for regulation of the elements from rat alpha 1-acid glycoprotein and beta-fibrinogen genes. J Biol Chem. 1990 Dec 25;265(36):22275–22281. [PubMed] [Google Scholar]
  5. Baumann H., Jahreis G. P., Morella K. K., Won K. A., Pruitt S. C., Jones V. E., Prowse K. R. Transcriptional regulation through cytokine and glucocorticoid response elements of rat acute phase plasma protein genes by C/EBP and JunB. J Biol Chem. 1991 Oct 25;266(30):20390–20399. [PubMed] [Google Scholar]
  6. 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]
  7. Bodmer B., Siboo R. Isolation of mouse C-reactive protein from liver and serum. J Immunol. 1977 Mar;118(3):1086–1089. [PubMed] [Google Scholar]
  8. Carthew R. W., Chodosh L. A., Sharp P. A. An RNA polymerase II transcription factor binds to an upstream element in the adenovirus major late promoter. Cell. 1985 Dec;43(2 Pt 1):439–448. doi: 10.1016/0092-8674(85)90174-6. [DOI] [PubMed] [Google Scholar]
  9. Ciliberto G., Arcone R., Wagner E. F., Rüther U. Inducible and tissue-specific expression of human C-reactive protein in transgenic mice. EMBO J. 1987 Dec 20;6(13):4017–4022. doi: 10.1002/j.1460-2075.1987.tb02745.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Costa R. H., Lai E., Grayson D. R., Darnell J. E., Jr The cell-specific enhancer of the mouse transthyretin (prealbumin) gene binds a common factor at one site and a liver-specific factor(s) at two other sites. Mol Cell Biol. 1988 Jan;8(1):81–90. doi: 10.1128/mcb.8.1.81. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Courtois G., Baumhueter S., Crabtree G. R. Purified hepatocyte nuclear factor 1 interacts with a family of hepatocyte-specific promoters. Proc Natl Acad Sci U S A. 1988 Nov;85(21):7937–7941. doi: 10.1073/pnas.85.21.7937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. 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]
  13. Fey G. H., Gauldie J. The acute phase response of the liver in inflammation. Prog Liver Dis. 1990;9:89–116. [PubMed] [Google Scholar]
  14. Frain M., Swart G., Monaci P., Nicosia A., Stämpfli S., Frank R., Cortese R. The liver-specific transcription factor LF-B1 contains a highly diverged homeobox DNA binding domain. Cell. 1989 Oct 6;59(1):145–157. doi: 10.1016/0092-8674(89)90877-5. [DOI] [PubMed] [Google Scholar]
  15. Ganapathi M. K., Rzewnicki D., Samols D., Jiang S. L., Kushner I. Effect of combinations of cytokines and hormones on synthesis of serum amyloid A and C-reactive protein in Hep 3B cells. J Immunol. 1991 Aug 15;147(4):1261–1265. [PubMed] [Google Scholar]
  16. Ganapathi M. K., Schultz D., Mackiewicz A., Samols D., Hu S. I., Brabenec A., Macintyre S. S., Kushner I. Heterogeneous nature of the acute phase response. Differential regulation of human serum amyloid A, C-reactive protein, and other acute phase proteins by cytokines in Hep 3B cells. J Immunol. 1988 Jul 15;141(2):564–569. [PubMed] [Google Scholar]
  17. Ganter U., Arcone R., Toniatti C., Morrone G., Ciliberto G. Dual control of C-reactive protein gene expression by interleukin-1 and interleukin-6. EMBO J. 1989 Dec 1;8(12):3773–3779. doi: 10.1002/j.1460-2075.1989.tb08554.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Gross-Bellard M., Oudet P., Chambon P. Isolation of high-molecular-weight DNA from mammalian cells. Eur J Biochem. 1973 Jul 2;36(1):32–38. doi: 10.1111/j.1432-1033.1973.tb02881.x. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Hocke G. M., Barry D., Fey G. H. Synergistic action of interleukin-6 and glucocorticoids is mediated by the interleukin-6 response element of the rat alpha 2 macroglobulin gene. Mol Cell Biol. 1992 May;12(5):2282–2294. doi: 10.1128/mcb.12.5.2282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. 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]
  23. Kilpatrick J. M., Volanakis J. E. Molecular genetics, structure, and function of C-reactive protein. Immunol Res. 1991;10(1):43–53. doi: 10.1007/BF02918166. [DOI] [PubMed] [Google Scholar]
  24. Kushner I. The acute phase response: an overview. Methods Enzymol. 1988;163:373–383. doi: 10.1016/0076-6879(88)63037-0. [DOI] [PubMed] [Google Scholar]
  25. Lassar A. B., Buskin J. N., Lockshon D., Davis R. L., Apone S., Hauschka S. D., Weintraub H. MyoD is a sequence-specific DNA binding protein requiring a region of myc homology to bind to the muscle creatine kinase enhancer. Cell. 1989 Sep 8;58(5):823–831. doi: 10.1016/0092-8674(89)90935-5. [DOI] [PubMed] [Google Scholar]
  26. Le P. T., Muller M. T., Mortensen R. F. Acute phase reactants of mice. I. Isolation of serum amyloid P-component (SAP) and its induction by a monokine. J Immunol. 1982 Aug;129(2):665–672. [PubMed] [Google Scholar]
  27. Lei K. J., Liu T., Zon G., Soravia E., Liu T. Y., Goldman N. D. Genomic DNA sequence for human C-reactive protein. J Biol Chem. 1985 Oct 25;260(24):13377–13383. [PubMed] [Google Scholar]
  28. Li S. P., Liu T. Y., Goldman N. D. cis-acting elements responsible for interleukin-6 inducible C-reactive protein gene expression. J Biol Chem. 1990 Mar 5;265(7):4136–4142. [PubMed] [Google Scholar]
  29. Li X. X., Liao W. S. Expression of rat serum amyloid A1 gene involves both C/EBP-like and NF kappa B-like transcription factors. J Biol Chem. 1991 Aug 15;266(23):15192–15201. [PubMed] [Google Scholar]
  30. Lin B. F., Ku N. O., Zahedi K., Whitehead A. S., Mortensen R. F. IL-1 and IL-6 mediate increased production and synthesis by hepatocytes of acute-phase reactant mouse serum amyloid P-component (SAP). Inflammation. 1990 Jun;14(3):297–313. doi: 10.1007/BF00915814. [DOI] [PubMed] [Google Scholar]
  31. Maire P., Wuarin J., Schibler U. The role of cis-acting promoter elements in tissue-specific albumin gene expression. Science. 1989 Apr 21;244(4902):343–346. doi: 10.1126/science.2711183. [DOI] [PubMed] [Google Scholar]
  32. Majello B., Arcone R., Toniatti C., Ciliberto G. Constitutive and IL-6-induced nuclear factors that interact with the human C-reactive protein promoter. EMBO J. 1990 Feb;9(2):457–465. doi: 10.1002/j.1460-2075.1990.tb08131.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Maniatis T., Goodbourn S., Fischer J. A. Regulation of inducible and tissue-specific gene expression. Science. 1987 Jun 5;236(4806):1237–1245. doi: 10.1126/science.3296191. [DOI] [PubMed] [Google Scholar]
  34. Mitchell P. J., Tjian R. Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins. Science. 1989 Jul 28;245(4916):371–378. doi: 10.1126/science.2667136. [DOI] [PubMed] [Google Scholar]
  35. Mueller C. R., Maire P., Schibler U. DBP, a liver-enriched transcriptional activator, is expressed late in ontogeny and its tissue specificity is determined posttranscriptionally. Cell. 1990 Apr 20;61(2):279–291. doi: 10.1016/0092-8674(90)90808-r. [DOI] [PubMed] [Google Scholar]
  36. Müller M. M., Ruppert S., Schaffner W., Matthias P. A cloned octamer transcription factor stimulates transcription from lymphoid-specific promoters in non-B cells. Nature. 1988 Dec 8;336(6199):544–551. doi: 10.1038/336544a0. [DOI] [PubMed] [Google Scholar]
  37. Nishiguchi S., Maeda S., Araki S., Shimada K. Structure of the mouse serum amyloid P component gene. Biochem Biophys Res Commun. 1988 Sep 30;155(3):1366–1373. doi: 10.1016/s0006-291x(88)81292-0. [DOI] [PubMed] [Google Scholar]
  38. Ohlsson H., Edlund T. Sequence-specific interactions of nuclear factors with the insulin gene enhancer. Cell. 1986 Apr 11;45(1):35–44. doi: 10.1016/0092-8674(86)90535-0. [DOI] [PubMed] [Google Scholar]
  39. Ohnishi S., Maeda S., Nishiguchi S., Arao T., Shimada K. Structure of the mouse C-reactive protein gene. Biochem Biophys Res Commun. 1988 Oct 31;156(2):814–822. doi: 10.1016/s0006-291x(88)80917-3. [DOI] [PubMed] [Google Scholar]
  40. Oliveira E. B., Gotschlich E. C., Liu T. Y. Comparative studies on the binding properties of human and rabbit C-reactive proteins. J Immunol. 1980 Mar;124(3):1396–1402. [PubMed] [Google Scholar]
  41. Oliviero S., Cortese R. The human haptoglobin gene promoter: interleukin-6-responsive elements interact with a DNA-binding protein induced by interleukin-6. EMBO J. 1989 Apr;8(4):1145–1151. doi: 10.1002/j.1460-2075.1989.tb03485.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Osmand A. P., Friedenson B., Gewurz H., Painter R. H., Hofmann T., Shelton E. Characterization of C-reactive protein and the complement subcomponent C1t as homologous proteins displaying cyclic pentameric symmetry (pentraxins). Proc Natl Acad Sci U S A. 1977 Feb;74(2):739–743. doi: 10.1073/pnas.74.2.739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Pepys M. B., Baltz M. L. Acute phase proteins with special reference to C-reactive protein and related proteins (pentaxins) and serum amyloid A protein. Adv Immunol. 1983;34:141–212. doi: 10.1016/s0065-2776(08)60379-x. [DOI] [PubMed] [Google Scholar]
  44. Pepys M. B. Isolation of serum amyloid P-component (protein SAP) in the mouse. Immunology. 1979 Jul;37(3):637–641. [PMC free article] [PubMed] [Google Scholar]
  45. Poli V., Cortese R. Interleukin 6 induces a liver-specific nuclear protein that binds to the promoter of acute-phase genes. Proc Natl Acad Sci U S A. 1989 Nov;86(21):8202–8206. doi: 10.1073/pnas.86.21.8202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Poli V., Mancini F. P., Cortese R. IL-6DBP, a nuclear protein involved in interleukin-6 signal transduction, defines a new family of leucine zipper proteins related to C/EBP. Cell. 1990 Nov 2;63(3):643–653. doi: 10.1016/0092-8674(90)90459-r. [DOI] [PubMed] [Google Scholar]
  47. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Scheidereit C., Cromlish J. A., Gerster T., Kawakami K., Balmaceda C. G., Currie R. A., Roeder R. G. A human lymphoid-specific transcription factor that activates immunoglobulin genes is a homoeobox protein. Nature. 1988 Dec 8;336(6199):551–557. doi: 10.1038/336551a0. [DOI] [PubMed] [Google Scholar]
  49. Schultz D. R., Arnold P. I. Properties of four acute phase proteins: C-reactive protein, serum amyloid A protein, alpha 1-acid glycoprotein, and fibrinogen. Semin Arthritis Rheum. 1990 Dec;20(3):129–147. doi: 10.1016/0049-0172(90)90055-k. [DOI] [PubMed] [Google Scholar]
  50. Simon J. A., Sutton C. A., Lobell R. B., Glaser R. L., Lis J. T. Determinants of heat shock-induced chromosome puffing. Cell. 1985 Apr;40(4):805–817. doi: 10.1016/0092-8674(85)90340-x. [DOI] [PubMed] [Google Scholar]
  51. Steel D. M., Whitehead A. S. Heterogeneous modulation of acute-phase-reactant mRNA levels by interleukin-1 beta and interleukin-6 in the human hepatoma cell line PLC/PRF/5. Biochem J. 1991 Jul 15;277(Pt 2):477–482. doi: 10.1042/bj2770477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Taylor A. W., Ku N. O., Mortensen R. F. Regulation of cytokine-induced human C-reactive protein production by transforming growth factor-beta. J Immunol. 1990 Oct 15;145(8):2507–2513. [PubMed] [Google Scholar]
  53. Toniatti C., Arcone R., Majello B., Ganter U., Arpaia G., Ciliberto G. Regulation of the human C-reactive protein gene, a major marker of inflammation and cancer. Mol Biol Med. 1990 Jun;7(3):199–212. [PubMed] [Google Scholar]
  54. Toniatti C., Demartis A., Monaci P., Nicosia A., Ciliberto G. Synergistic trans-activation of the human C-reactive protein promoter by transcription factor HNF-1 binding at two distinct sites. EMBO J. 1990 Dec;9(13):4467–4475. doi: 10.1002/j.1460-2075.1990.tb07897.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Tsai S. F., Martin D. I., Zon L. I., D'Andrea A. D., Wong G. G., Orkin S. H. Cloning of cDNA for the major DNA-binding protein of the erythroid lineage through expression in mammalian cells. Nature. 1989 Jun 8;339(6224):446–451. doi: 10.1038/339446a0. [DOI] [PubMed] [Google Scholar]
  56. Tsutsumi K., Ito K., Ishikawa K. Developmental appearance of transcription factors that regulate liver-specific expression of the aldolase B gene. Mol Cell Biol. 1989 Nov;9(11):4923–4931. doi: 10.1128/mcb.9.11.4923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Vaulont S., Puzenat N., Levrat F., Cognet M., Kahn A., Raymondjean M. Proteins binding to the liver-specific pyruvate kinase gene promoter. A unique combination of known factors. J Mol Biol. 1989 Sep 20;209(2):205–219. doi: 10.1016/0022-2836(89)90273-8. [DOI] [PubMed] [Google Scholar]
  58. Whitehead A. S., Rits M., Michaelson J. Molecular genetics of mouse serum amyloid P component (SAP): cloning and gene mapping. Immunogenetics. 1988;28(5):388–390. doi: 10.1007/BF00364241. [DOI] [PubMed] [Google Scholar]
  59. Whitehead A. S., Zahedi K., Rits M., Mortensen R. F., Lelias J. M. Mouse C-reactive protein. Generation of cDNA clones, structural analysis, and induction of mRNA during inflammation. Biochem J. 1990 Feb 15;266(1):283–290. doi: 10.1042/bj2660283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Wigler M., Pellicer A., Silverstein S., Axel R. Biochemical transfer of single-copy eucaryotic genes using total cellular DNA as donor. Cell. 1978 Jul;14(3):725–731. doi: 10.1016/0092-8674(78)90254-4. [DOI] [PubMed] [Google Scholar]
  61. Wilson D. R., Juan T. S., Wilde M. D., Fey G. H., Darlington G. J. A 58-base-pair region of the human C3 gene confers synergistic inducibility by interleukin-1 and interleukin-6. Mol Cell Biol. 1990 Dec;10(12):6181–6191. doi: 10.1128/mcb.10.12.6181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Xiao H., Lis J. T. Germline transformation used to define key features of heat-shock response elements. Science. 1988 Mar 4;239(4844):1139–1142. doi: 10.1126/science.3125608. [DOI] [PubMed] [Google Scholar]
  63. Yunis I., Whitehead A. S. The mouse C-reactive protein gene maps to distal chromosome 1 and, like its human counterpart, is closely linked to the serum amyloid P component gene. Immunogenetics. 1990;32(5):361–363. doi: 10.1007/BF00211651. [DOI] [PubMed] [Google Scholar]
  64. de Simone V., Cortese R. The transcriptional regulation of liver-specific gene expression. Oxf Surv Eukaryot Genes. 1988;5:51–90. [PubMed] [Google Scholar]

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