Aw. Wyke et al., UNCOUPLING OF THE PATHWAYS WHICH LINK MAP KINASE TO C-FOS TRANSCRIPTION AND AP-1 IN RESPONSE TO GROWTH STIMULI, Cellular signalling, 8(2), 1996, pp. 131-139
The v-Src oncoprotein induces mitogenesis and transformation of cells
through multiple effects on diverse signalling pathways that are influ
enced by the cellular context in which v-Src is expressed. Here we hav
e examined the effects of a temperature-sensitive (ts) v-Src on transc
ription of the c-fos proto-oncogene, in serum-deprived and growing Rat
-1 fibroblasts. We have also considered the role of mitogen-activated
protein (MAP) kinase, a known mediator of ternary complex formation at
the c-fos serum response element (SRE), which results in transcriptio
nal enhancement in response to growth factors. In cells exponentially
growing in the presence of serum, activation of v-Src stimulated MAP k
inase and c-fos transcription. In cells made quiescent by serum depriv
ation, however, v-Src did not induce a c-fos transcriptional response,
nor was there stimulation of ternary complex formation, despite norma
l activation of MAP kinase. Thus, activation of MAP kinase and stimula
tion of c-fos transcription and ternary complex formation are uncouple
d in the absence of serum growth factors. Stimulation of c-fos by v-Sr
c in growing cells, however, coincided with formation of a complex wit
h an oligonucleotide spanning the c-Sis-inducible element (SIE) upstre
am from the SRE, suggesting that the signal transduction and activator
of transcription (STAT) family of transcription factors, which bind h
ere, may function in response to the v-Src oncoprotein. During these s
tudies, we also observed that addition of fresh serum growth factors t
o growing Rat-1 fibroblasts expressing ts v-Src at the restrictive tem
perature resulted in substantially impaired activation of MAP kinase.
This interference with normal growth factor signalling implies that ca
talytically inactive Src acts in a dominant negative manner by blockin
g normal activation of MAP kinase, although not at the expense of c-fo
s transcription. Thus, serum-induced c-fos transcription can also occu
r in an MAP kinase-independent manner.