Abstract
Transcription of the macrophage scavenger receptor A gene is markedly upregulated during monocyte to macrophage differentiation. In these studies, we demonstrate that 291 bp of the proximal scavenger receptor promoter, in concert with a 400-bp upstream enhancer element, is sufficient to direct macrophage-specific expression of a human growth hormone reporter in transgenic mice. These regulatory elements, which contain binding sites for PU.1, AP-1, and cooperating ets-domain transcription factors, are also sufficient to mediate regulation of transgene expression during the in vitro differentiation of bone marrow progenitor cells in response to macrophage colony-stimulating factor. Mutation of the PU.1 binding site within the scavenger receptor promoter severely impairs transgene expression, consistent with a crucial role of PU.1 in regulating the expression of the scavenger receptor gene. The ability of the scavenger receptor promoter and enhancer to target gene expression to macrophages in vivo, including foam cells of atherosclerotic lesions, suggests that these regulatory elements will be of general utility in the study of macrophage differentiation and function by permitting specific modifications of macrophage gene expression.
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- 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]
- 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]
- Daley G. Q., Van Etten R. A., Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990 Feb 16;247(4944):824–830. doi: 10.1126/science.2406902. [DOI] [PubMed] [Google Scholar]
- Dejager S., Mietus-Snyder M., Friera A., Pitas R. E. Dominant negative mutations of the scavenger receptor. Native receptor inactivation by expression of truncated variants. J Clin Invest. 1993 Aug;92(2):894–902. doi: 10.1172/JCI116664. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Endemann G., Stanton L. W., Madden K. S., Bryant C. M., White R. T., Protter A. A. CD36 is a receptor for oxidized low density lipoprotein. J Biol Chem. 1993 Jun 5;268(16):11811–11816. [PubMed] [Google Scholar]
- Fogelman A. M., Haberland M. E., Seager J., Hokom M., Edwards P. A. Factors regulating the activities of the low density lipoprotein receptor and the scavenger receptor on human monocyte-macrophages. J Lipid Res. 1981 Sep;22(7):1131–1141. [PubMed] [Google Scholar]
- 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]
- Gu H., Marth J. D., Orban P. C., Mossmann H., Rajewsky K. Deletion of a DNA polymerase beta gene segment in T cells using cell type-specific gene targeting. Science. 1994 Jul 1;265(5168):103–106. doi: 10.1126/science.8016642. [DOI] [PubMed] [Google Scholar]
- Henriksen T., Mahoney E. M., Steinberg D. Enhanced macrophage degradation of low density lipoprotein previously incubated with cultured endothelial cells: recognition by receptors for acetylated low density lipoproteins. Proc Natl Acad Sci U S A. 1981 Oct;78(10):6499–6503. doi: 10.1073/pnas.78.10.6499. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Kamps M. P., Baltimore D. E2A-Pbx1, the t(1;19) translocation protein of human pre-B-cell acute lymphocytic leukemia, causes acute myeloid leukemia in mice. Mol Cell Biol. 1993 Jan;13(1):351–357. doi: 10.1128/mcb.13.1.351. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Krieger M., Herz J. Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). Annu Rev Biochem. 1994;63:601–637. doi: 10.1146/annurev.bi.63.070194.003125. [DOI] [PubMed] [Google Scholar]
- Lira S. A., Crenshaw E. B., 3rd, Glass C. K., Swanson L. W., Rosenfeld M. G. Identification of rat growth hormone genomic sequences targeting pituitary expression in transgenic mice. Proc Natl Acad Sci U S A. 1988 Jul;85(13):4755–4759. doi: 10.1073/pnas.85.13.4755. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Metcalf D. The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells. Nature. 1989 May 4;339(6219):27–30. doi: 10.1038/339027a0. [DOI] [PubMed] [Google Scholar]
- Moulton K. S., Semple K., Wu H., Glass C. K. Cell-specific expression of the macrophage scavenger receptor gene is dependent on PU.1 and a composite AP-1/ets motif. Mol Cell Biol. 1994 Jul;14(7):4408–4418. doi: 10.1128/mcb.14.7.4408. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- 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]
- 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]
- O'Neill E. M., Rebay I., Tjian R., Rubin G. M. The activities of two Ets-related transcription factors required for Drosophila eye development are modulated by the Ras/MAPK pathway. Cell. 1994 Jul 15;78(1):137–147. doi: 10.1016/0092-8674(94)90580-0. [DOI] [PubMed] [Google Scholar]
- Ottnad E., Parthasarathy S., Sambrano G. R., Ramprasad M. P., Quehenberger O., Kondratenko N., Green S., Steinberg D. A macrophage receptor for oxidized low density lipoprotein distinct from the receptor for acetyl low density lipoprotein: partial purification and role in recognition of oxidatively damaged cells. Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1391–1395. doi: 10.1073/pnas.92.5.1391. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Palinski W., Ord V. A., Plump A. S., Breslow J. L., Steinberg D., Witztum J. L. ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum. Arterioscler Thromb. 1994 Apr;14(4):605–616. doi: 10.1161/01.atv.14.4.605. [DOI] [PubMed] [Google Scholar]
- Palmiter R. D., Brinster R. L., Hammer R. E., Trumbauer M. E., Rosenfeld M. G., Birnberg N. C., Evans R. M. Dramatic growth of mice that develop from eggs microinjected with metallothionein-growth hormone fusion genes. Nature. 1982 Dec 16;300(5893):611–615. doi: 10.1038/300611a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pitas R. E., Innerarity T. L., Weinstein J. N., Mahley R. W. Acetoacetylated lipoproteins used to distinguish fibroblasts from macrophages in vitro by fluorescence microscopy. Arteriosclerosis. 1981 May-Jun;1(3):177–185. doi: 10.1161/01.atv.1.3.177. [DOI] [PubMed] [Google Scholar]
- Plump A. S., Smith J. D., Hayek T., Aalto-Setälä K., Walsh A., Verstuyft J. G., Rubin E. M., Breslow J. L. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992 Oct 16;71(2):343–353. doi: 10.1016/0092-8674(92)90362-g. [DOI] [PubMed] [Google Scholar]
- 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]
- Sauer B., Henderson N. Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5166–5170. doi: 10.1073/pnas.85.14.5166. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Scott E. W., Simon M. C., Anastasi J., Singh H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science. 1994 Sep 9;265(5178):1573–1577. doi: 10.1126/science.8079170. [DOI] [PubMed] [Google Scholar]
- Takahashi K., Naito M., Kodama T., Suzuki H., Mori T., Matsumoto A. Expression of macrophage scavenger receptors in various human tissues and atherosclerotic lesions. Clin Biochem. 1992 Oct;25(5):365–368. doi: 10.1016/0009-9120(92)80018-c. [DOI] [PubMed] [Google Scholar]
- Wu H., Moulton K., Horvai A., Parik S., Glass C. K. Combinatorial interactions between AP-1 and ets domain proteins contribute to the developmental regulation of the macrophage scavenger receptor gene. Mol Cell Biol. 1994 Mar;14(3):2129–2139. doi: 10.1128/mcb.14.3.2129. [DOI] [PMC free article] [PubMed] [Google Scholar]
- de Rijke Y. B., van Berkel T. J. Rat liver Kupffer and endothelial cells express different binding proteins for modified low density lipoproteins. Kupffer cells express a 95-kDa membrane protein as a specific binding site for oxidized low density lipoproteins. J Biol Chem. 1994 Jan 14;269(2):824–827. [PubMed] [Google Scholar]