Regulation of CSF-1 receptor expression

Area of Science:

• * Molecular Biology
• * Developmental Biology
• * Immunology

Background:

• * Macrophage colony-stimulating factor (CSF-1) receptor, encoded by the c-fms protooncogene, regulates mononuclear phagocyte survival, growth, differentiation, and function.
• * The c-fms gene serves as a macrophage differentiation marker, with distinct expression patterns during embryonic development.

Purpose of the Study:

• * To investigate the cis-acting elements and transcriptional regulation of the c-fms promoter.
• * To explore the role of transcription factors Pu.1 and c-Ets-2 in c-fms gene expression.
• * To analyze c-fms promoter activity in various cell types, including tumor cell lines.

Main Methods:

• * Whole mount mRNA expression analysis in embryos to determine c-fms expression patterns.
• * Studies of cis-acting elements of the c-fms promoter, including the role of PU box elements.
• * Coexpression assays with transcription factors Pu.1 and c-Ets-2.
• * Analysis of c-fms promoter activity in diverse tumor cell lines, including serum responsiveness and Ras pathway interactions.

Main Results:

• * c-fms is highly expressed in embryonic placental trophoblasts and detectable in yolk sac and embryonic cells from 8.5-10.5 days postcoitus.
• * The c-fms promoter activity relies on the collaboration between Pu.1 and other Ets transcription factors, with two PU box elements sufficient for macrophage-specific promotion.
• * Synergistic activation of the c-fms promoter by Pu.1 and c-Ets-2 was observed.
• * A 3.5kb c-fms exon 2 promoter showed activity in various tumor cell lines, except melanoma K1735 where it induced growth arrest. This promoter was serum-responsive and inducible by coexpression of the c-fms product.
• * Unlike other CSF-1/c-fms-responsive promoters, the c-fms promoter was not responsive to activated Ras.
• * In Lewis lung carcinoma cells, an intronic terminator was overcome, leading to detectable c-fms and macrophage-specific gene expression under serum deprivation.

Conclusions:

• * The c-fms promoter's regulation involves a complex interplay of transcription factors, particularly Pu.1 and c-Ets-2, common in macrophage-specific gene expression.
• * The c-fms promoter exhibits differential activity and regulation in various cell types, including tumor cells, suggesting context-dependent roles.
• * Aberrant c-fms expression in certain tumor contexts, like melanoma and Lewis lung carcinoma, highlights its potential involvement in cancer biology.