1987; Phan-Dinh-Tuy et al. 1988; Rivera et al. 1990; Walsh 1989). In A431 
cells the SRF has a mildly inducible DNA-binding activity (Prywes and Roeder 
1986), but in general this factor appears to be constitutiveiy bound to the 
CArG box (Herrera et al. 1989; Treisman 1986). Although the SRF is a 
phosphoprotein, to date no phosphorylation changes have been shown that 
correlate with the induction of the c -fos gene. It is likely that the SRF is the 
anchoring member of a complex of factors that bind to the SRE. One such 
factor that has been characterized is p62 TCF (for ternary complex factor), which 
appears to bind to the SRE only in conjunction with the SRF and makes 
contacts with the 5' side of the SRE (Schroter et al. 1990; Shaw et al. 1989a). 
Mutations in the 5' flank of the dyad symmetry region (outside the CArG box) 
reduce the ability of the SRE to confer responses to phorbol esters, but these 
same mutant elements still retain the ability to respond to serum (Graham 
and Gilman 1991; Shaw et al. 1989a). In addition, the SRE can mediate 
autorepression of c-fos transcription (Konig et al. 1989; Sassone-Corsi et 
al. 1988a; Shaw et al. 1989b). Cotransfection of a constitutiveiy produced 
c -fos gene with a reporter gene that is driven by the SRE greatly reduces the 
expression of a linked reporter gene. Thus, the rapid burst of transcription of 
c -fos can be explained by the fact that the activation of the c -fos promoter 
stimulates production of the c-Fos protein, which is then able to repress its own 
transcription. It is not yet known whether this repression is a direct or indirect 
effect. The C terminus of the c-Fos protein is required for this repression and is 
often mutated in the viral form of the gene (Ofir et al. 1990). Understanding the 
transcription factor complexes that bind near and around the SRE is essential 
for understanding the regulation of c-fos and several other early-response 
genes (de Belle et al. 1991). 
Upstream of the SRE at -346 is a sequence called the sis/PDGF-inducible 
factor (SIF) element. A transcription factor with an inducible DNA-binding 
activity specifically binds to this element after treatment of 3T3 cells with PDGF 
(Hayes et al. 1987). Genomic footprinting indicates that in A431 cells treated 
with EGF there is also an inducible DNA-binding activity that interacts with this 
element (Herrera et al. 1989). The SIF element confers induction onto the c-fos 
promoter in the absence of the SRE but responds specifically to PDGF and not 
to serum or phorbol esters (Wagner et al. 1990). 
Most of these regulatory elements are capable of showing some activity outside 
of the context of the fos promoter. However, the context within which they lie is 
important as well. For instance, the SIF element requires sequences between 
-222 and -1 00 of the c-fos gene to respond to PDGF. Furthermore, moving the 
SRE closer to the promoter weakens its response to PDGF and phorbol esters 
but not its response to serum (Wagner et al. 1990). Moreover, there are cell 
type-specific differences in the ability of these elements to respond to a given 
11 
