pmc logo image
Logo of pnasPNAS Home page.Reference to the article.PNAS Info for AuthorsPNAS SubscriptionsPNAS About

Formats:

Proc Natl Acad Sci U S A. 1995 June 6; 92(12): 5391–5395.
PMCID: PMC41700
Scavenger receptor A gene regulatory elements target gene expression to macrophages and to foam cells of atherosclerotic lesions.
A Horvai, W Palinski, H Wu, K S Moulton, K Kalla, and C K Glass
Division of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA.
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.
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 (2.0M), 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.
  • 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. [PubMed]
  • 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. [PubMed]
  • 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. [PubMed]
  • Endemann G, Stanton LW, Madden KS, Bryant CM, White RT, Protter AA. CD36 is a receptor for oxidized low density lipoprotein. J Biol Chem. 1993 Jun 5;268(16):11811–11816. [PubMed]
  • de Rijke YB, van Berkel TJ. 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]
  • Ottnad E, Parthasarathy S, Sambrano GR, Ramprasad MP, 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. [PubMed]
  • Henriksen T, Mahoney EM, 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. [PubMed]
  • 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. [PubMed]
  • Fogelman AM, Haberland ME, Seager J, Hokom M, Edwards PA. 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]
  • 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]
  • Clinton SK, Underwood R, Hayes L, Sherman ML, Kufe DW, 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. [PubMed]
  • Metcalf D. The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells. Nature. 1989 May 4;339(6219):27–30. [PubMed]
  • Moulton KS, Wu H, Barnett J, Parthasarathy S, Glass CK. 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. [PubMed]
  • Moulton KS, Semple K, Wu H, Glass CK. 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. [PubMed]
  • Wu H, Moulton K, Horvai A, Parik S, Glass CK. 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. [PubMed]
  • Scott EW, Simon MC, 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. [PubMed]
  • Bortner DM, Ulivi M, Roussel MF, Ostrowski MC. 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. [PubMed]
  • 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]
  • O'Neill EM, Rebay I, Tjian R, Rubin GM. 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. [PubMed]
  • Palmiter RD, Brinster RL, Hammer RE, Trumbauer ME, Rosenfeld MG, Birnberg NC, Evans RM. Dramatic growth of mice that develop from eggs microinjected with metallothionein-growth hormone fusion genes. Nature. 1982 Dec 16;300(5893):611–615. [PubMed]
  • Lira SA, Crenshaw EB, 3rd, Glass CK, Swanson LW, Rosenfeld MG. 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. [PubMed]
  • Daley GQ, Van Etten RA, 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. [PubMed]
  • Kamps MP, 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. [PubMed]
  • Pitas RE, Innerarity TL, Weinstein JN, Mahley RW. Acetoacetylated lipoproteins used to distinguish fibroblasts from macrophages in vitro by fluorescence microscopy. Arteriosclerosis. 1981 May–Jun;1(3):177–185. [PubMed]
  • Dejager S, Mietus-Snyder M, Friera A, Pitas RE. Dominant negative mutations of the scavenger receptor. Native receptor inactivation by expression of truncated variants. J Clin Invest. 1993 Aug;92(2):894–902. [PubMed]
  • Goldstein JL, Ho YK, Basu SK, Brown MS. 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. [PubMed]
  • Plump AS, Smith JD, Hayek T, Aalto-Setälä K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992 Oct 16;71(2):343–353. [PubMed]
  • Palinski W, Ord VA, Plump AS, Breslow JL, Steinberg D, Witztum JL. 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. [PubMed]
  • 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. [PubMed]
  • 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. [PubMed]
  • Gu H, Marth JD, Orban PC, 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. [PubMed]