title: Uncoupling of the pathways which link MAP kinase to c-fos transcription and AP-1 in response to growth stimuli.
abstract: The v-Src oncoprotein induces mitogenesis and transformation of cells through multiple effects on diverse signalling pathways that are influenced by the cellular context in which v-Src is expressed. Here we have examined the effects of a temperature-sensitive (ts) v-Src on transcription 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 transcriptional enhancement in response to growth factors. In cells exponentially growing in the presence of serum, activation of v-Src stimulated MAP kinase and c-fos transcription. In cells made quiescent by serum deprivation, however, v-Src did not induce a c-fos transcriptional response, nor was there stimulation of ternary complex formation, despite normal activation of MAP kinase. Thus, activation of MAP kinase and stimulation of c-fos transcription and ternary complex formation are uncoupled in the absence of serum growth factors. Stimulation of c-fos by v-Src in growing cells, however, coincided with formation of a complex with an oligonucleotide spanning the c-Sis-inducible element (SIE) upstream from the SRE, suggesting that the signal transduction and activator of transcription (STAT) family of transcription factors, which bind here, may function in response to the v-Src oncoprotein. During these studies, we also observed that addition of fresh serum growth factors to growing Rat-1 fibroblasts expressing ts v-Src at the restrictive temperature resulted in substantially impaired activation of MAP kinase. This interference with normal growth factor signalling implies that catalytically inactive Src acts in a dominant negative manner by blocking normal activation of MAP kinase, although not at the expense of c-fos transcription. Thus, serum-induced c-fos transcription can also occur in an MAP kinase-independent manner.
authors.affiliation: Beatson Institute for Cancer Research, CRC Beatson Laboratories, Bearsden, UK.
authors.forename: A W
authors.initials: AW
authors.lastname: Wyke
authors.forename: A
authors.initials: A
authors.lastname: Lang
authors.forename: M C
authors.initials: MC
authors.lastname: Frame
mesh_terms: D000818:Animals; D001483:Base Sequence; D001798:Blood Proteins / Q000494:pharmacology; D015152:Blotting, Northern; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002460:Cell Line / Q000166:cytology / Q000201:enzymology; D004268:DNA-Binding Proteins / Q000502:physiology; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D016762:Genes, fos / Q000235:genetics*; D016391:Genes, src / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D015398:Signal Transduction / Q000235:genetics; D013696:Temperature; D018808:Transcription Factor AP-1 / Q000235:genetics*; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D001798:Blood Proteins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D017871:Calcium-Calmodulin-Dependent Protein Kinases