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. 1994 Mar;14(3):2129–2139. doi: 10.1128/mcb.14.3.2129

Combinatorial interactions between AP-1 and ets domain proteins contribute to the developmental regulation of the macrophage scavenger receptor gene.

H Wu 1, K Moulton 1, A Horvai 1, S Parik 1, C K Glass 1
PMCID: PMC358573  PMID: 8114743

Abstract

Macrophage development is regulated by a complex set of hormone-like molecules and cell adhesion events that control the growth and differentiation of progenitor cells. The macrophage scavenger receptor (SR) gene becomes markedly upregulated during the final stages of monocyte-to-macrophage differentiation and provides a model for the identification and characterization of transcription factors that control this process. In this report, we have identified three genomic regulatory elements that are required for transactivation of the SR gene in the THP-1 monocytic leukemia cell line following induction of macrophage differentiation by tetradecanoyl phorbol acetate. Each of these regulatory elements contains a near-consensus binding site for members of the AP-1 gene family, while the two most quantitatively important elements also contain juxtaposed binding sites for ets domain transcription factors. We demonstrate that tetradecanoyl phorbol acetate treatment results in a marked and prolonged increase in AP-1 binding activity on these elements, which can be accounted for almost entirely by c-jun and junB. These proteins in turn form ternary complexes with additional factors that bind to the adjacent ets recognition motifs. Several indirect lines of evidence indicate that ets2 represents a component of this ternary complex. The combined expression of c-jun, ets2, and a constitutive form of ras result in synergistic increases in transcription from promoters containing the SR regulatory elements. These observations suggest that SR gene expression is regulated via a signal transduction pathway involving ras, AP-1, and ets domain proteins and imply that at least some of the signalling components involved in ras-dependent growth are also utilized to promote the expression of genes involved in terminal differentiation.

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Selected References

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  1. Adunyah S. E., Unlap T. M., Wagner F., Kraft A. S. Regulation of c-jun expression and AP-1 enhancer activity by granulocyte-macrophage colony-stimulating factor. J Biol Chem. 1991 Mar 25;266(9):5670–5675. [PubMed] [Google Scholar]
  2. Angel P., Hattori K., Smeal T., Karin M. The jun proto-oncogene is positively autoregulated by its product, Jun/AP-1. Cell. 1988 Dec 2;55(5):875–885. doi: 10.1016/0092-8674(88)90143-2. [DOI] [PubMed] [Google Scholar]
  3. Angel P., Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta. 1991 Dec 10;1072(2-3):129–157. doi: 10.1016/0304-419x(91)90011-9. [DOI] [PubMed] [Google Scholar]
  4. Auwerx J. H., Deeb S., Brunzell J. D., Peng R., Chait A. Transcriptional activation of the lipoprotein lipase and apolipoprotein E genes accompanies differentiation in some human macrophage-like cell lines. Biochemistry. 1988 Apr 19;27(8):2651–2655. doi: 10.1021/bi00408a003. [DOI] [PubMed] [Google Scholar]
  5. Boise L. H., Petryniak B., Mao X., June C. H., Wang C. Y., Lindsten T., Bravo R., Kovary K., Leiden J. M., Thompson C. B. The NFAT-1 DNA binding complex in activated T cells contains Fra-1 and JunB. Mol Cell Biol. 1993 Mar;13(3):1911–1919. doi: 10.1128/mcb.13.3.1911. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bortner D. M., Ulivi M., Roussel M. F., Ostrowski M. C. The carboxy-terminal catalytic domain of the GTPase-activating protein inhibits nuclear signal transduction and morphological transformation mediated by the CSF-1 receptor. Genes Dev. 1991 Oct;5(10):1777–1785. doi: 10.1101/gad.5.10.1777. [DOI] [PubMed] [Google Scholar]
  7. Bruder J. T., Heidecker G., Rapp U. R. Serum-, TPA-, and Ras-induced expression from Ap-1/Ets-driven promoters requires Raf-1 kinase. Genes Dev. 1992 Apr;6(4):545–556. doi: 10.1101/gad.6.4.545. [DOI] [PubMed] [Google Scholar]
  8. Chen C., Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. doi: 10.1128/mcb.7.8.2745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chiu R., Angel P., Karin M. Jun-B differs in its biological properties from, and is a negative regulator of, c-Jun. Cell. 1989 Dec 22;59(6):979–986. doi: 10.1016/0092-8674(89)90754-x. [DOI] [PubMed] [Google Scholar]
  10. Clinton S. K., Underwood R., Hayes L., Sherman M. L., Kufe D. W., Libby P. Macrophage colony-stimulating factor gene expression in vascular cells and in experimental and human atherosclerosis. Am J Pathol. 1992 Feb;140(2):301–316. [PMC free article] [PubMed] [Google Scholar]
  11. Datta R., Imamura K., Goldman S. J., Dianoux A. C., Kufe D. W., Sherman M. L. Functional expression of the macrophage colony-stimulating factor receptor in human THP-1 monocytic leukemia cells. Blood. 1992 Feb 15;79(4):904–912. [PubMed] [Google Scholar]
  12. Datta R., Sherman M. L., Stone R. M., Kufe D. Expression of the jun-B gene during induction of monocytic differentiation. Cell Growth Differ. 1991 Jan;2(1):43–49. [PubMed] [Google Scholar]
  13. Deng T., Karin M. JunB differs from c-Jun in its DNA-binding and dimerization domains, and represses c-Jun by formation of inactive heterodimers. Genes Dev. 1993 Mar;7(3):479–490. doi: 10.1101/gad.7.3.479. [DOI] [PubMed] [Google Scholar]
  14. Fraser I., Hughes D., Gordon S. Divalent cation-independent macrophage adhesion inhibited by monoclonal antibody to murine scavenger receptor. Nature. 1993 Jul 22;364(6435):343–346. doi: 10.1038/364343a0. [DOI] [PubMed] [Google Scholar]
  15. Freeman M., Ekkel Y., Rohrer L., Penman M., Freedman N. J., Chisolm G. M., Krieger M. Expression of type I and type II bovine scavenger receptors in Chinese hamster ovary cells: lipid droplet accumulation and nonreciprocal cross competition by acetylated and oxidized low density lipoprotein. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4931–4935. doi: 10.1073/pnas.88.11.4931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fujita T., Shibuya H., Ohashi T., Yamanishi K., Taniguchi T. Regulation of human interleukin-2 gene: functional DNA sequences in the 5' flanking region for the gene expression in activated T lymphocytes. Cell. 1986 Aug 1;46(3):401–405. doi: 10.1016/0092-8674(86)90660-4. [DOI] [PubMed] [Google Scholar]
  17. Glass C. K., Holloway J. M., Devary O. V., Rosenfeld M. G. The thyroid hormone receptor binds with opposite transcriptional effects to a common sequence motif in thyroid hormone and estrogen response elements. Cell. 1988 Jul 29;54(3):313–323. doi: 10.1016/0092-8674(88)90194-8. [DOI] [PubMed] [Google Scholar]
  18. Goldstein J. L., Ho Y. K., Basu S. K., Brown M. S. Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci U S A. 1979 Jan;76(1):333–337. doi: 10.1073/pnas.76.1.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gégonne A., Bosselut R., Bailly R. A., Ghysdael J. Synergistic activation of the HTLV1 LTR Ets-responsive region by transcription factors Ets1 and Sp1. EMBO J. 1993 Mar;12(3):1169–1178. doi: 10.1002/j.1460-2075.1993.tb05758.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hara H., Tanishita H., Yokoyama S., Tajima S., Yamamoto A. Induction of acetylated low density lipoprotein receptor and suppression of low density lipoprotein receptor on the cells of human monocytic leukemia cell line (THP-1 cell). Biochem Biophys Res Commun. 1987 Jul 31;146(2):802–808. doi: 10.1016/0006-291x(87)90601-2. [DOI] [PubMed] [Google Scholar]
  21. Imamura K., Dianoux A., Nakamura T., Kufe D. Colony-stimulating factor 1 activates protein kinase C in human monocytes. EMBO J. 1990 Aug;9(8):2423-8, 2389. doi: 10.1002/j.1460-2075.1990.tb07418.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Imler J. L., Schatz C., Wasylyk C., Chatton B., Wasylyk B. A Harvey-ras responsive transcription element is also responsive to a tumour-promoter and to serum. Nature. 1988 Mar 17;332(6161):275–278. doi: 10.1038/332275a0. [DOI] [PubMed] [Google Scholar]
  23. Ishibashi S., Inaba T., Shimano H., Harada K., Inoue I., Mokuno H., Mori N., Gotoda T., Takaku F., Yamada N. Monocyte colony-stimulating factor enhances uptake and degradation of acetylated low density lipoproteins and cholesterol esterification in human monocyte-derived macrophages. J Biol Chem. 1990 Aug 25;265(24):14109–14117. [PubMed] [Google Scholar]
  24. Jain J., McCaffrey P. G., Valge-Archer V. E., Rao A. Nuclear factor of activated T cells contains Fos and Jun. Nature. 1992 Apr 30;356(6372):801–804. doi: 10.1038/356801a0. [DOI] [PubMed] [Google Scholar]
  25. Klemsz M. J., McKercher S. R., Celada A., Van Beveren C., Maki R. A. The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell. 1990 Apr 6;61(1):113–124. doi: 10.1016/0092-8674(90)90219-5. [DOI] [PubMed] [Google Scholar]
  26. Kodama T., Freeman M., Rohrer L., Zabrecky J., Matsudaira P., Krieger M. Type I macrophage scavenger receptor contains alpha-helical and collagen-like coiled coils. Nature. 1990 Feb 8;343(6258):531–535. doi: 10.1038/343531a0. [DOI] [PubMed] [Google Scholar]
  27. Kovary K., Bravo R. The jun and fos protein families are both required for cell cycle progression in fibroblasts. Mol Cell Biol. 1991 Sep;11(9):4466–4472. doi: 10.1128/mcb.11.9.4466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kryszke M. H., Piette J., Yaniv M. Induction of a factor that binds to the polyoma virus A enhancer on differentiation of embryonal carcinoma cells. Nature. 1987 Jul 16;328(6127):254–256. doi: 10.1038/328254a0. [DOI] [PubMed] [Google Scholar]
  29. Kunkel T. A. Rapid and efficient site-specific mutagenesis without phenotypic selection. Proc Natl Acad Sci U S A. 1985 Jan;82(2):488–492. doi: 10.1073/pnas.82.2.488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Langer S. J., Bortner D. M., Roussel M. F., Sherr C. J., Ostrowski M. C. Mitogenic signaling by colony-stimulating factor 1 and ras is suppressed by the ets-2 DNA-binding domain and restored by myc overexpression. Mol Cell Biol. 1992 Dec;12(12):5355–5362. doi: 10.1128/mcb.12.12.5355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lin A., Frost J., Deng T., Smeal T., al-Alawi N., Kikkawa U., Hunter T., Brenner D., Karin M. Casein kinase II is a negative regulator of c-Jun DNA binding and AP-1 activity. Cell. 1992 Sep 4;70(5):777–789. doi: 10.1016/0092-8674(92)90311-y. [DOI] [PubMed] [Google Scholar]
  32. Moulton K. S., Wu H., Barnett J., Parthasarathy S., Glass C. K. Regulated expression of the human acetylated low density lipoprotein receptor gene and isolation of promoter sequences. Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8102–8106. doi: 10.1073/pnas.89.17.8102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Naito M., Kodama T., Matsumoto A., Doi T., Takahashi K. Tissue distribution, intracellular localization, and in vitro expression of bovine macrophage scavenger receptors. Am J Pathol. 1991 Dec;139(6):1411–1423. [PMC free article] [PubMed] [Google Scholar]
  34. Nakamura T., Datta R., Kharbanda S., Kufe D. Regulation of jun and fos gene expression in human monocytes by the macrophage colony-stimulating factor. Cell Growth Differ. 1991 Jun;2(6):267–272. [PubMed] [Google Scholar]
  35. Nakamura T., Lin L. L., Kharbanda S., Knopf J., Kufe D. Macrophage colony stimulating factor activates phosphatidylcholine hydrolysis by cytoplasmic phospholipase A2. EMBO J. 1992 Dec;11(13):4917–4922. doi: 10.1002/j.1460-2075.1992.tb05598.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Pongubala J. M., Nagulapalli S., Klemsz M. J., McKercher S. R., Maki R. A., Atchison M. L. PU.1 recruits a second nuclear factor to a site important for immunoglobulin kappa 3' enhancer activity. Mol Cell Biol. 1992 Jan;12(1):368–378. doi: 10.1128/mcb.12.1.368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Pulverer B. J., Kyriakis J. M., Avruch J., Nikolakaki E., Woodgett J. R. Phosphorylation of c-jun mediated by MAP kinases. Nature. 1991 Oct 17;353(6345):670–674. doi: 10.1038/353670a0. [DOI] [PubMed] [Google Scholar]
  38. Reddy M. A., Langer S. J., Colman M. S., Ostrowski M. C. An enhancer element responsive to ras and fms signaling pathways is composed of two distinct nuclear factor binding sites. Mol Endocrinol. 1992 Jul;6(7):1051–1060. doi: 10.1210/mend.6.7.1324418. [DOI] [PubMed] [Google Scholar]
  39. Rohrer L., Freeman M., Kodama T., Penman M., Krieger M. Coiled-coil fibrous domains mediate ligand binding by macrophage scavenger receptor type II. Nature. 1990 Feb 8;343(6258):570–572. doi: 10.1038/343570a0. [DOI] [PubMed] [Google Scholar]
  40. Sherr C. J. Regulation of mononuclear phagocyte proliferation by colony-stimulating factor-1. Int J Cell Cloning. 1990 Jan;8 (Suppl 1):46–62. doi: 10.1002/stem.5530080706. [DOI] [PubMed] [Google Scholar]
  41. Smeal T., Binetruy B., Mercola D. A., Birrer M., Karin M. Oncogenic and transcriptional cooperation with Ha-Ras requires phosphorylation of c-Jun on serines 63 and 73. Nature. 1991 Dec 12;354(6353):494–496. doi: 10.1038/354494a0. [DOI] [PubMed] [Google Scholar]
  42. Sweet R. W., Yokoyama S., Kamata T., Feramisco J. R., Rosenberg M., Gross M. The product of ras is a GTPase and the T24 oncogenic mutant is deficient in this activity. Nature. 1984 Sep 20;311(5983):273–275. doi: 10.1038/311273a0. [DOI] [PubMed] [Google Scholar]
  43. Tong L. A., de Vos A. M., Milburn M. V., Jancarik J., Noguchi S., Nishimura S., Miura K., Ohtsuka E., Kim S. H. Structural differences between a ras oncogene protein and the normal protein. Nature. 1989 Jan 5;337(6202):90–93. doi: 10.1038/337090a0. [DOI] [PubMed] [Google Scholar]
  44. Varticovski L., Druker B., Morrison D., Cantley L., Roberts T. The colony stimulating factor-1 receptor associates with and activates phosphatidylinositol-3 kinase. Nature. 1989 Dec 7;342(6250):699–702. doi: 10.1038/342699a0. [DOI] [PubMed] [Google Scholar]
  45. Vojtek A. B., Hollenberg S. M., Cooper J. A. Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell. 1993 Jul 16;74(1):205–214. doi: 10.1016/0092-8674(93)90307-c. [DOI] [PubMed] [Google Scholar]
  46. Warne P. H., Viciana P. R., Downward J. Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature. 1993 Jul 22;364(6435):352–355. doi: 10.1038/364352a0. [DOI] [PubMed] [Google Scholar]
  47. Wasylyk B., Hahn S. L., Giovane A. The Ets family of transcription factors. Eur J Biochem. 1993 Jan 15;211(1-2):7–18. doi: 10.1007/978-3-642-78757-7_2. [DOI] [PubMed] [Google Scholar]
  48. Wasylyk B., Wasylyk C., Flores P., Begue A., Leprince D., Stehelin D. The c-ets proto-oncogenes encode transcription factors that cooperate with c-Fos and c-Jun for transcriptional activation. Nature. 1990 Jul 12;346(6280):191–193. doi: 10.1038/346191a0. [DOI] [PubMed] [Google Scholar]
  49. Watson D. K., McWilliams M. J., Lapis P., Lautenberger J. A., Schweinfest C. W., Papas T. S. Mammalian ets-1 and ets-2 genes encode highly conserved proteins. Proc Natl Acad Sci U S A. 1988 Nov;85(21):7862–7866. doi: 10.1073/pnas.85.21.7862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Zhang X. F., Settleman J., Kyriakis J. M., Takeuchi-Suzuki E., Elledge S. J., Marshall M. S., Bruder J. T., Rapp U. R., Avruch J. Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature. 1993 Jul 22;364(6435):308–313. doi: 10.1038/364308a0. [DOI] [PubMed] [Google Scholar]
  51. de Wet J. R., Wood K. V., DeLuca M., Helinski D. R., Subramani S. Firefly luciferase gene: structure and expression in mammalian cells. Mol Cell Biol. 1987 Feb;7(2):725–737. doi: 10.1128/mcb.7.2.725. [DOI] [PMC free article] [PubMed] [Google Scholar]

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