Related Experiment Videos
The v-fms oncogene induces factor independence and tumorigenicity in CSF-1 dependent macrophage cell line
Abstract:
The McDonough strain of feline sarcoma virus (SM-FeSV) transforms fibroblast cell lines in culture and produces fibrosarcomas in domestic cats. SM-FeSV does not induce haematopoietic malignancies in spite of the fact that its viral oncogene, v-fms, codes for a glycoprotein related to the receptor for the mononuclear phagocyte colony stimulating factor, CSF-1. The v-fms-coded polypeptide includes the complete extracellular domain of the c-fms proto-oncogene product and retains the ability to bind CSF-1 specifically. The two molecules have very similar sequences except at their extreme carboxyl terminal ends where 40 amino acids of the c-fms-coded glycoprotein are replaced by 11 unrelated residues in the v-fms product. Autophosphorylation of the c-fms gene product on tyrosine is enhanced by CSF-1 addition, whereas phosphorylation of the v-fms-coded glycoprotein appears to be constitutive. We now show that introduction of the v-fms gene into simian virus-40 (SV40)-immortalized, CSF-1 dependent macrophages renders them independent of CSF-1 for growth and tumourigenic in nude mice. These factor-independent cell lines express unaltered levels of the c-fms product which is down-modulated in response to either CSF-1 or the tumour promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). The induction of factor independence by a non-autocrine mechanism suggests that the v-fms product is an unregulated kinase that provides growth stimulatory signals in the absence of ligand.
Insights
Feline sarcoma virus (SM-FeSV) oncogene v-fms confers CSF-1 independence and tumorogenicity to macrophages. This suggests v-fms acts as an unregulated kinase, driving cell growth without external signals.
Area of Science:
- Virology
- Molecular Biology
- Oncology
Background:
- Feline sarcoma virus (SM-FeSV) causes fibrosarcomas but not hematopoietic malignancies.
- Its oncogene, v-fms, encodes a CSF-1 receptor-like glycoprotein.
- v-fms shares sequence similarity with c-fms but has altered C-terminal residues.
Purpose of the Study:
- To investigate the function of the v-fms oncogene in macrophage transformation.
- To determine if v-fms confers growth factor independence and tumorogenicity.
- To elucidate the mechanism of v-fms-mediated transformation.
Main Methods:
- Introduction of the v-fms gene into SV40-immortalized macrophages.
- Assessing CSF-1 dependence for growth and tumorogenicity in nude mice.
- Analyzing c-fms product levels and phosphorylation status.
Main Results:
- v-fms expression rendered macrophages CSF-1 independent and tumorogenic.
- These cells maintained unaltered c-fms product levels.
- CSF-1 and TPA induced down-modulation of the c-fms product.
Conclusions:
- The v-fms product functions as a constitutively active, unregulated tyrosine kinase.
- This leads to ligand-independent growth factor signaling and transformation.
- SM-FeSV transformation mechanism involves dysregulation of the c-fms pathway.