The c-fms proto-oncogene encodes the receptor for a hematopoietic growth factor, CSF-1. There has been increasing recognition of c-fms and its ligand CSF-1 in malignancies of non-hematopoietic origin, such as breast and ovarian cancers. We initially studied breast carcinoma cell lines in which dexamethasone (dex) treatment results in marked overexpression of both c-fms steady-state transcript and protein levels. Our results of c-fms mRNA stability and transcription rate are compatible with regulation of c-fms expression by dex at the post-transcriptional level. Induction of c-fms is dependent on transcription of a glucocorticoid responsive factor. Our results indicate that this factor may be a regulatory protein which stabilizes c-fms transcripts, leading to c-fms overexpression. In this application, we focus on first elucidating the c-fms transcript sequence responsible for mRNA stability upon exposure to dex, and then characterizing the RNA-protein complex and binding site important to stabilization and overexpression of the c-fms transcript. We propose to use methodologies which have been employed to define other sequences important to glucocorticoid inducible mRNA stability and those used to characterize other protein-RNA regulatory complexes, such as the AUUUA-specific mRNA binding protein. A greater understanding of the mechanism underlying regulation of the c-fms proto-oncogene is important, as both c-fms and its ligand CSF-1 appear to contribute to the invasive phenotype and/or poor prognosis associated with carcinomas of breast, ovarian, endometrial, and placental origin. Elucidation of such a sequence, which may represent a consensus sequence through which c-fms expression is regulated, would lead to development of therapeutic strategies which interfere with protein binding to this site, resulting in downregulation of c-fms expression.
| Chambers, Setsuko K; Ivins, Christina M; Kacinski, Barry M et al. (2004) An unexpected effect of glucocorticoids on stimulation of c-fms proto-oncogene expression in choriocarcinoma cells that express little glucocorticoid receptor. Am J Obstet Gynecol 190:974-85 |
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