Regulation of CSF-1 receptor expression

Abstract

Cells of the mononuclear phagocyte lineage possess receptors for macrophage colony‐stimulating factor (CSF‐1) encoded by the c‐fms protooncogene and respond to CSF‐1 with increased survival, growth, differentiation, and reversible changes in function. The c‐fms gene is itself a macrophage differentiation marker. In whole mount analyses of mRNA expression in embryos, c‐fms is expressed at very high levels on placental trophoblasts. It is detectable on individual cells in the yolk sac around 8.5 to 9 days postcoitus, appears on isolated cells in the head of the embryo around 9.5 dpc, and appears on numerous cells throughout the embryo by day 10.5. The extent of c‐fms expression is much greater than for other macrophage‐specific genes including lysozyme and a macrophage‐specific protein tyrosine phosphatase. Our studies of the cis‐acting elements of the c‐fms promoter have indicated a key role for collaboration between the macrophage‐specific transcription factor, Pu. 1, which functions in determining the site of transcription initiation, and other members of the Ets transcription factor family. This is emerging as a common pattern in macrophage specific promoters. We have shown that two PU box elements alone can function as a macrophage‐specific promoter. The activity of both the artifical promoter and the c‐fms promoter is activated synergistically by coexpression of Pu. 1 and another Ets factor, c‐Ets‐2. A 3.5kb c‐fms exon 2 promoter (but not the 300bp proximal promoter) is also active in a wide diversity of tumor cell lines. The interesting exception is the melanoma cell line K1735, in which the promoter is completely shut down and expression of c‐fms causes growth arrest and cell death. The activity of the exon 2 promoter in these nonmacrophages is at least as serum responsive as the classic serum‐responsive promoter of the c‐fos gene. It is further inducible in nonmacrophages by coexpression of the c‐fms product. Unlike other CSF‐1/c‐fms‐responsive promoters, the c‐fms promoter is not responsive to activated Ras even when c‐Ets‐2 is coexpressed. In most lines, production of full length c‐fms is prevented by a downstream intronic terminator, but in Lewis lung carcinoma, read‐through does occur, and expression of both c‐fms and other macrophage‐specific genes such as lysozyme and urokinase becomes detectable in conditions of serum deprivation. Mol Reprod Dev 46:46–53, 1997. © 1997 Wiley‐Liss, Inc.

Adipocyte macrophage colony-stimulating factor is a mediator of adipose tissue growth.

“…We propose that the mechanism by which MCSF mediates adipose tissue hyperplasia is comparable to the effects of MCSF in other cell systems, particularly those where c-fms expression occurs concurrently (35). Furthermore, we speculate that adipocyte TNF-␣ (19,20), in part, modulates the effects of MCSF, as we demonstrated in adipocytes in vitro and as has been reported elsewhere (22,23).…”

Bone Marrow Angiotensin AT 1 Receptor Regulates Differentiation of Monocyte Lineage Progenitors From Hematopoietic Stem Cells

“…The M-CSF receptor c-Fms is encoded by the c-fms protooncogene, 26 whose expression is predominantly regulated by the transcription factor Pu.1. 27 Agtr1 Ϫ/Ϫ mice do not show any phenotype of low growth rate, tooth deficiency, severe osteopetrosis, reduced bone marrow cellularity, or Ϫ/Ϫ mice is primarily attributable to the impaired TNF-␣-mediated actions.…”

The Runx1 transcription factor controls CSF-1-dependent and -independent growth and survival of macrophages

“…Surface CSF-1R, and c-fms mRNA expression is relatively low in macrophages exposed to saturating amounts of CSF-1, and is inducible upon CSF-1 removal (Hume et al, 1997). The mechanism of this feedback loop has not previously been identified.…”