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Molecular and Cellular Biology, September 1998, p. 5073-5081, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

The C-Terminal Domain of c-fos Is Required for Activation of an AP-1 Site Specific for jun-fos Heterodimers

Kevin McBride and Mona Nemer*

Laboratoire de Developpement et Différenciation Cardiaques, Institut de Recherches Cliniques de Montréal, and Département de Pharmacologie, Université de Montréal, Montréal, Québec, Canada H2W 1R7

Received 21 April 1998/Returned for modification 28 May 1998/Accepted 3 June 1998

The proto-oncogenes jun and fos are members of the AP-1 family of transcription factors, which activate transcription of target genes via the tetradecanoyl phorbol acetate response element (TRE). Both jun and fos contain activation domains, but their relative contributions to transcriptional activation of different TREs remain unclear. It is not apparent whether the cellular availability of specific AP-1 members is the major determinant for regulation of TREs or whether other factors including the TRE sequence itself contribute to selectivity. We have identified in the promoter of the rat atrial natriuretic factor (ANF) a novel AP-1 site which is unresponsive to jun homodimers and is inducible only in the presence of c-fos. This activation is potentiated by mitogen-activated protein (MAP) kinase. The jun proteins appear to be required solely to tether c-fos to the promoter, and c-fos mutants lacking 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 at this specialized AP-1 site. Mutations within the C terminus of c-fos at serine residues that are phosphorylation targets for growth factors and MAP kinase completely abrogate transactivation and block potentiation by MAP kinase. Using GAL4 fusions, we show that the 90-amino-acid C terminus of c-fos contains autonomous activation domains and that the serine residues are essential for full activity. These results suggest that phosphorylation of the C terminus of c-fos affects its transactivation properties and provide evidence for novel regulatory mechanisms that may contribute to biologic specificities of the AP-1 transcription complex.

* Corresponding author. Mailing address: Laboratoire de développement et différenciation cardiaques, Institut de recherches cliniques de Montréal, 110 des Pins Ouest, Montréal, QC, Canada H2W 1R7. Phone: (514) 987-5680. Fax: (514) 987-5575. E-mail: nemerm{at}ircm.umontreal.ca.

Molecular and Cellular Biology, September 1998, p. 5073-5081, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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