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Mol. Cell. Biol. doi:10.1128/MCB.01489-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Extracellular signals regulate rapid coactivator recruitment at AP-1 sites by altered phosphorylation of both CREB binding protein (CBP) and c-jun proteins

University of Illinois Cancer Center, 801 S. Paulina Street, Room 530C, MC860, Chicago, IL 60612

	Abstract

Retinoic acid (RA) inhibits matrix metalloproteinase 9 (MMP-9) expression due to AP-1 inhibition resulting from RARs competing for limiting amounts of coactivator proteins. However given the rapid kinetics of MMP-9 transcription, it seems unlikely that these interactions can be explained passively. Our previous studies indicated that coactivator and transcription factor phosphorylation may allow for rapid regulation of MMP-9 expression. In the present study we tested this hypothesis directly. CBP and PCAF were displaced from transcription factor binding sites on the MMP-9 promoter within minutes of RA treatment. The RAR interaction domains of CBP and PCAF were not required for this displacement. RA and EGF had opposing effects on phosphorylation of CBP by ERK1 which correlated with altered CBP occupancy of AP-1 sites and differential MMP-9 promoter activation. We identified a novel phosphorylation site in the CBP carboxyl terminus that mediated association with AP-1 sites in the MMP-9 promoter. Inhibition of c-jun phosphorylation displaced PCAF from AP-1 sites and reduced promoter activity. Phosphorylation deficient c-jun was less able to recruit PCAF to AP-1 sites. We also demonstrated novel interactions between coactivators and AP-1 proteins. We propose that extracellular signal mediated coactivator exchange at AP-1 sites is mediated via protein kinase pathways.