Important note: Information in this article was accurate in 1990. The state of the art may have changed since the publication date.
TRANSFORMING POTENTIAL OF THE C-FMS PROTO-ONCOGENE
Diss Abstr Int [B]; 50(8):3270 1990. Unique Identifier : AIDSLINE ICDB/90665098 Woolford J; Univ. of Washington
Abstract:
c-fms is the gene encoding the receptor for the hematopoietic growth factor M-CSF. It was initially identified as the cellular homologue of v-fms, the retroviral oncogene carried by the Susan McDonough and Hardy-Zuckerman 5 strains of feline sarcoma virus. v-fms is capable of producing fibrosarcomas in vivo and transforming cells in culture. In contrast, the c-fms proto-oncogene is non-transforming. In this dissertation I have characterized the c-fms gene product and determined the changes required to activate its transforming ability. Using antisera directed against the v-fms gene product c-fms glycoproteins of approximately 125 and 140 kDa were detected in human choriocarcinoma cells and mature monocytes. Pulse-chase analysis revealed that, as is the case with the v-fms gene product, the 140 kDa protein was derived from the 125 kDa precursor. However, in contrast to the viral protein, the c-fms gene product was efficiently processed with essentially all of the molecules being converted into the mature 140 kDa species. As was previously shown with the viral protein, gp120/140c-fms was shown to have an associated in vitro tyrosine specific protein kinase activity; however, in vivo, only phosphoserine and phosphothreonine were detected on gp120/140c-fms. To determine the changes that activated the transforming ability of fms, a feline c-fms cDNA was cloned, sequenced, and used to make chimeric c/v-fms constructs. The viral and cellular proteins differ by nine amino acid changes and the loss of 50 C-terminal residues from v-fms and their replacement with eleven novel residues. The C-terminal modification alone resulted in only a very weakly transforming gene, but the addition of point mutations at amino acid positions 301 and 374 produced a fully transformed phenotype which was indistinguishable from that of v-fms. These point mutations are presumed to alter the conformation of the extra-cellular domain in such a way to mimic ligand binding. Thus far v-fms is the only tyrosine-kinase growth factor receptor to be activated by such a mechanism.
Keywords: Amino Acid Sequence Cell Transformation, Neoplastic/*GENETICS Cells, Cultured Cloning, Molecular Human HIV Envelope Protein gp120/GENETICS Phenotype Proto-Oncogene Proteins/*GENETICS *Proto-Oncogenes Retroviridae Proteins, Oncogenic/GENETICS Tumor Cells, Cultured THESIS 900630
M9060633
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Important note: Information in this article was accurate in 1990. The state of the art may have changed since the publication date.
