Scavenger receptor A gene regulatory elements target gene expression to macrophages and to foam cells of atherosclerotic lesions.
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.
Horvai
A
A
Division of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0651, USA.
Palinski
W
W
Wu
H
H
Moulton
K S
KS
Kalla
K
K
Glass
C K
CK
D000818:Animals; D001161:Arteriosclerosis / Q000235:genetics*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005487:Foam Cells / Q000378:metabolism*; D018390:Gene Targeting; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011971:Receptors, Immunologic / Q000235:genetics*; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D012045:Regulatory Sequences, Nucleic Acid; D051122:Scavenger Receptors, Class B
D008565:Membrane Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B