Signal integration at the c-fos promoter.

The c-fos gene encodes a basic region-leucine zipper transcription factor that requires heterodimerization with a member of the Jun family for stable DNA binding. Fos/Jun heterodimers are present in the AP-1 transcription factor complex and both c-Fos and c-Jun are capable of transforming cells (1). Continuous expression of c-fos can lead to aberrant differentiation (2) but may also sometimes block differentiation (3). Furthermore, antisense c-fos RNA or microinjected Fosspecific antibodies are able to inhibit cell growth (4—6). The study of the regulation of the c-fos gene may therefore provide important clues as to how cellular differentiation and proliferation are controlled. The c-fos proto-oncogene is a member of the class of cellular immediate early genes which are rapidly and transiently induced upon stimulation of quiescent cells with growth factors or serum (7-9). In addition to these mitogens, many nonmitogenic signals such as UV-light (10) can also induce c-fos in a similar fashion. This transcriptional induction is independent of de novo synthesized proteins and inhibition of protein synthesis leads to an even stronger and prolonged induction of c-fos (11), indicating that components already exist for signal transduction cascades which target the c-fos promoter. Three proximal elements within the c-fos promoter have been identified as major targets for stimulating signals (Figure 1): the sis inducible element (SIE*) (12,13), the serum response element (SRE) (14,15) and the cAMP response element (CRE) (15). In the following, the pathways and mechanisms of signaling to these three promoter elements and their binding proteins will be discussed.