Induction of sustained expression of proto-oncogene c-fms by platelet-derived growth factor, epidermal growth factor, and basic fibroblast growth factor, and its suppression by interferon-gamma and macrophage colony-stimulating factor in human aortic medial smooth muscle cells.

Abstract

Vascular medial smooth muscle cells migrate, proliferate and transform to foam cells in the process of atherosclerosis. We have reported that the intimal smooth muscle cells express proto-oncogene c-fms, a characteristic gene of monocyte-macrophages, which is not normally expressed in medial smooth muscle cells. In the present study, we demonstrated that combinations of platelet-derived growth factor (PDGF)-BB and either epidermal growth factor (EGF) or fibroblast growth factor (FGF) induced high expression of c-fms in normal human medial smooth muscle cells to the level of intimal smooth muscle cells or monocyte-derived macrophages, whereas c-fins expression by PDGF-BB alone was 1/1o and both EGF and FGF had no independent effect Invest. 1995Invest. . 95:1133Invest. -1139

Genetic Instability, DNA Damage and Atherosclerosis

“…10,11 Furthermore, it has been reported that overexpression of PDGF, c-myc and other protooncogenes occurs in atherosclerotic vascular lesions. [11][12][13] The monoclonal hypothesis is also consistent with the observations that carcinogenic agents, like chemical mutagens, radiations and oncogenic viruses, can induce atherosclerotic lesions in laboratory animals and have atherogenic effects in human population. 2,[14][15][16][17][18][19] Certainly, the "response to injury" and the "monoclonal" theories of atherosclerosis are not mutually exclusive and can be unified as described in Figure 2.…”

Transcription Factor PU.1 Mediates Induction of c-fms in Vascular Smooth Muscle Cells: a Mechanism for Phenotypic Change to Phagocytic Cells

“…The human M-CSF receptor (c-fms) monocytic promoter (5.3-kb KpnI-NcoI fragment of c-fms genomic DNA) was kindly provided by C. J. Sherr and was extended at its 3Ј end to within 2 bp upstream of the translation start site. This fragment was digested with either EcoRI or SacI, and the resultant 1.2-kb EcoRI-NcoI and 599-bp SacI-NcoI fragments, after being rendered blunt ended by T4 DNA polymerase, were cloned into a chloramphenicol acetyltransferase (CAT) plasmid (pBS-CAT) that had been digested with EcoRV (12,15,25). Both fragments contain 179 bp of exon 2.…”

“…Twenty-five micrograms of total RNA was hybridized with approximately 20,000 cpm of the RNA probe overnight at 42ЊC and then was digested with the mixture of RNase A and RNase T 1 . A specific RNA for human scavenger receptor that was protected from digestion was separated on a 5% acrylamide-8 M urea gel (15).…”

“…We have shown that the combination of platelet-derived growth factor (PDGF)-BB with either epidermal growth factor (EGF) or fibroblast growth factor induces high levels of expression of c-fms in normal human medial smooth muscle cells to the extent apparent in intimal smooth muscle cells derived from atherosclerotic lesions or in monocyte-derived macrophages (15,16). To investigate the mechanism by which growth factors induce c-fms expression in normal vascular smooth muscle cells, we have now examined the activity of the c-fms promoter and its interaction with transcription factors.…”

“…After 8 h, the culture medium was replaced with DMEM containing 10% FBS. After a further 56 h, the cells were incubated sequentially with serum-free medium for 24 h and with both PDGF-BB (10 ng/ml) and EGF (3 ng/ml) for 8 h. Finally, the cells were harvested for measurement of CAT (11) and ␤-galactosidase (14) activities as described previously (15). The CAT activity was standardized relative to ␤-galactosidase activity.…”