Oncogene N-ras mediates selective inhibition of c-fos induction by nerve growth factor and basic fibroblast growth factor in a PC12 cell line.
A cell line was generated from U7 cells (a subline of PC12 rat pheochromocytoma cells) that contains a stably integrated transforming mouse N-ras (Lys-61) gene under the control of the long terminal repeat from mouse mammary tumor virus. Such cells, designated UR61, undergo neuronal differentiation upon exposure to nanomolar concentrations of dexamethasone, as a consequence of expression of the activated N-ras gene (I. Guerrero, A. Pellicer, and D.E. Burstein, Biochem, Biophys. Res. Commun. 150:1185-1192, 1988). Exposure of UR61 cells to either nerve growth factor (NGF) or basic fibroblast growth factor (bFGF) results in a marked induction of c-fos RNA, with kinetics paralleling those of NGF- or bFGF-induced expression of c-fos RNA in PC12 cells. Dexamethasone-induced expression of activated N-ras p21 results in blocking of c-fos RNA induction by NGF or bFGF in a time-dependent manner. Activated N-ras p21-mediated inhibition of c-fos RNA induction in UR61 cells is selective for NGF and bFGF and is not due to selective degradation of c-fos RNA. Normal and transforming N-ras can trans activate the chloramphenicol acetyltransferase gene linked to mouse c-fos regulatory sequences when transient expression assays are performed. Our observations suggest that N-ras p21 selectively interacts with pathways involved in induction of c-fos expression which initiate at the receptors for NGF and bFGF.
Thomson
T M
TM
Department of Pathology, New York University Medical Center, New York 10016.
Green
S H
SH
Trotta
R J
RJ
Burstein
D E
DE
Pellicer
A
A
D000310:Adrenal Gland Neoplasms; D000818:Animals; D002460:Cell Line; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D011905:Genes, ras; D009414:Nerve Growth Factors / Q000494:pharmacology*; D010673:Pheochromocytoma; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos; D011519:Proto-Oncogenes / Q000187:drug effects
D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D005346:Fibroblast Growth Factors; D011505:Protein-Tyrosine Kinases