Post-transcriptional regulation of c-fms proto-oncogene expression by dexamethasone and of CSF-1 in human breast carcinomas in vitro.
The c-fms proto-oncogene encodes the receptor for a hematopoietic growth factor, CSF-1. Recently, the importance of c-fms and its ligand CSF-1 in malignancies of non-hematopoietic origin, such as breast, ovarian, endometrial, pulmonary, and trophoblastic cancers has been recognized. We have previously shown that glucocorticoids induce a large increase in c-fms mRNA and protein levels in breast carcinoma cell lines. In this report, we investigate the mechanism underlying such c-fms overexpression by dexamethasone. We show that dexamethasone treatment of two breast carcinoma cell lines (BT20-c-fms expressor, and SKBR3-co-expressor of both c-fms and CSF-1) does not increase the rate of c-fms gene transcription, suggesting a post-transcriptional mechanism of regulation of c-fms expression by dexamethasone. The effect of protein synthesis inhibition was studied to help determine whether there was a role for intermediary regulatory proteins in the regulation of c-fms expression. We find that several protein synthesis inhibitors interfere with dexamethasone induction of c-fms transcripts, suggesting the existence of regulatory proteins. These regulatory proteins do not appear to be constitutively expressed, as we show no effect of protein synthesis inhibition on c-fms transcript expression in resting BT20 cells. These findings suggest that the putative regulatory proteins are induced by dexamethasone. Furthermore, the addition of a protein synthesis inhibitor, pactamycin, to dexamethasone-treated BT20 cells results in a decrease in c-fms mRNA stability.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520-8063.
S K
SK
Chambers
Y
Y
Wang
M
M
Gilmore-Hebert
B M
BM
Kacinski
D000581:Amidohydrolases; D000626:Aminopeptidases / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D010142:Pactamycin / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D014407:Tumor Cells, Cultured
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D010142:Pactamycin; D003907:Dexamethasone; D016173:Macrophage Colony-Stimulating Factor; D000626:Aminopeptidases; D000581:Amidohydrolases; C084507:peptide deformylase