TFII-I Enhances Activation of the c-fosPromoter through Interactions with Upstream Elements

ABSTRACT

The transcription factor TFII-I was initially isolated as a factor that can bind to initiator elements in core promoters. Recent evidence suggests that TFII-I may also have a role in signal transduction. We have found that overexpression of TFII-I can enhance the response of the wild-type c-fos promoter to a variety of stimuli. This effect depends on the c-fosc-sis–platelet-derived growth factor-inducible factor binding element (SIE) and serum response element (SRE). There is no effect of cotransfected TFII-I on the TATA box containing the c-fos basal promoter. Three TFII-I binding sites can be found in c-fos promoter. Two of these overlap the c-fos SIE and SRE, and another is located just upstream of the TATA box. Mutations that distinguish between serum response factor (SRF), STAT, and TFII-I binding to the c-fos SIE and SRE suggest that the binding of TFII-I to these elements is important for c-fos induction in conjunction with the SRF and STAT transcription factors. Moreover, TFII-I can form in vivo protein-protein complexes with the c-fos upstream activators SRF, STAT1, and STAT3. These results suggest that TFII-I may mediate the functional interdependence of the c-fos SIE and SRE elements. In addition, the ras pathway is required for TFII-I to exert its effects on the c-fos promoter, and growth factor stimulation enhances tyrosine phosphorylation of TFII-I. These results indicate that TFII-I is involved in signal transduction as well as transcriptional activation of the c-fospromoter.

ACKNOWLEDGMENTS

We are grateful to Beth Harvat, Kip Wharton, Peter Shaw, Larry Feig, and Richard Treisman for providing some of the plasmids used in these experiments. We thank Deepa Bhavsar for preparing the antisera to the STAT proteins and Daniel Ortiz for helpful advice. We thank Dorre Grueneberg and Michael Gilman for sharing unpublished results.

This work was supported by awards from the Concern Foundation for Cancer Research and the American Cancer Society (RPG-98-104-01-TBE) to A.L.R. and by NIH grant R01-GM51551 to B.H.C.