REGULATION OF THE C-FOS PROMOTER BY THE TERNARY COMPLEX FACTOR SAP-1AAND ITS COACTIVATOR CBP

The c-fos proto-oncogene is activated by a plethora of signals via the transcription factors Sap-1a and CREB. Recently, the coactivator CBP has been demonstrated to act in concert with CREB when CREB is phospho rylated by protein kinase A. We show that CBP also binds directly to S ap-1a. While phosphorylation of Sap-1a by mitogen-activated protein ki nases is not necessary for CBP/Sap-1a interaction, functional cooperat ion between these two proteins requires Sap-1a to become phosphorylate d. CBP-antagonists impair Sap-1a-mediated transactivation. Similarly, the CBP antagonist E1A suppresses c-fos upregulation by phosphorylated CREB, indicating that CBP is a central component of c-fos regulation. Furthermore, CBP is phosphorylated by protein kinase A in vitro and t he transactivation potential of the carboxyterminal region of CBP is e nhanced in the presence of active protein kinase A in vivo. Thus, CBP, in addition to CREB, is a target for cAMP-dependent signaling. Howeve r, combined phosphorylation of CBP by protein kinase A and mitogen-act ivated protein kinases appears to be non-cooperative, suggesting that CBP serves the function of a dampening integrator of two different sig naling pathways.