Regulation of CSF-1 receptor expression

Mol Reprod Dev. 1997 Jan;46(1):46-52; discussion 52-3. doi: 10.1002/(SICI)1098-2795(199701)46:1<46::AID-MRD8>3.0.CO;2-R.

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 artificial 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line
  • Gene Expression Regulation, Developmental*
  • Humans
  • Macrophages / metabolism
  • Molecular Sequence Data
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins / physiology
  • RNA, Messenger / biosynthesis
  • Receptor, Macrophage Colony-Stimulating Factor / biosynthesis*
  • Receptor, Macrophage Colony-Stimulating Factor / genetics
  • Sequence Alignment
  • Species Specificity
  • Trans-Activators / physiology
  • Transcription Factors / physiology
  • Transcription, Genetic

Substances

  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Trans-Activators
  • Transcription Factors
  • proto-oncogene protein Spi-1
  • Receptor, Macrophage Colony-Stimulating Factor