THE C-TERMINAL DOMAIN OF C-FOS IS REQUIRED FOR ACTIVATION OF AN AP-1 SITE-SPECIFIC FOR JUN-FOS HETERODIMERS

The proto-oncogenes jun and fos are members of the AP-1 family of tran scription factors, which activate transcription of target genes via th e tetradecanoyl phorbol acetate response element (TRE). Both jun and f os contain activation domains, but their relative contributions to tra nscriptional activation of different TREs remain unclear. It is not ap parent whether the cellular availability of specific AP-1 members is t he major determinant for regulation of TREs or whether other factors i ncluding the TRE sequence itself contribute to selectivity. We have id entified in the promoter of the rat atrial natriuretic factor (ANF) a novel AP-1 site which is unresponsive to jun homodimers and is inducib le only in the presence of c-fos. This activation is potentiated by mi togen-activated protein (MAP) kinase. The jun proteins appear to be re quired solely to tether c-fos to the promoter, and c-fos mutants lacki ng putative activation domains abrogate transactivation. Unexpectedly, the oncogenic form of c-fos which diverges most significantly in the carboxy-terminal 50 amino acids is unable to mediate transactivation a t this specialized AP-1 site. Mutations within the C terminus of c-fos at serine residues that are phosphorylation targets for growth factor s and MAP kinase completely abrogate transactivation and block potenti ation by MAP kinase. Using GAL4 fusions, we show that the 90-amino-aci d C terminus of c-fos contains autonomous activation domains and that the serine residues are essential for full activity. These results sug gest that phosphorylation of the C terminus of c-fos affects its trans activation properties and provide evidence for novel regulatory mechan isms that may contribute to biologic specificities of the AP-1 transcr iption complex.