SIF-E 
SRE AP-1 
P- 
AP-1? 
JEL. 
Rb-E2F 
Ca/CRE 
-JB^S 
TATA 
-350 
-300 
I 
-222 
“I 
-100 
-57 
FIGURE 1 . The structure of the c-fos promoter. See text for explanation of 
each element. 
Upstream of this element at approximately -100 are two direct repeat elements 
that also have multiple functions. There is evidence that these elements are 
involved in maintenance of basal expression of c-fos (Fisch et al. 1987; Gilman 
et al. 1986; Runkel et al. 1991). In addition, sequences that contain these 
elements have been shown to be responsive to a cotransfected retinoblastoma 
gene. Overexpression of the retinoblastoma gene can repress transcription 
of fos through this site (Robbins et al. 1990). Recently, it has been suggested 
that the transcription factor E2F, which was originally characterized as a factor 
that bound upstream of adenovirus early genes that are transactivated by the 
adenovirus transforming gene El A, can bind to the retinoblastoma responsive 
element (Chellappan et al. 1991). This is of interest since it has been shown 
that E2F can form a complex with the retinoblastoma gene product. 
Furthermore, E2F has a serum-stimulated DNA-binding activity and is involved 
in the regulation of other serum-inducible genes in fibroblasts, including c -myc 
and dihydrofolate reductase (Blake and Azizkhan 1989; Mudryj et al. 1990). 
However, although these two intriguing factors interact with this site, it has 
not yet been shown that this element plays a crucial role in the response of c- 
fos to extracellular stimuli such as growth factors, phorbol esters, and cAMP. 
Moreover, it is quite clear that c -fos is readily inducible in cells that contain 
a functional retinoblastoma gene product and that only overexpression of 
retinoblastoma causes a repression of fos in a transient assay. Further 
upstream, at -200 and -290, are two potential AP-1 sites. The one at -290 
has been shown to be functional and can bind proteins other than the Fos/ 
Jun family complex (Fisch et al. 1989b; Velcich and Ziff 1990). 
Centered around -31 0 of the human c -fos promoter is a region of dyad 
symmetry that has been termed the “serum response element” (SRE). It 
has been shown that this element is sufficient by itself to mediate induction 
of a heterologous gene by serum and phorbol esters (Gilman et al. 1986; 
Greenberg et al. 1987; Treisman 1985). The serum response factor (SRF) 
is a 67-kd phosphoprotein that binds to the core of the dyad symmetry element 
(Gilman et al. 1986; Norman et al. 1988; Treisman 1987). This core region has 
been called a CArG box and is also found upstream of several other early- 
response genes as well as in muscle-specific enhancers (Miwa and Kedes 
10 
