Extracellular Signals Regulate Rapid Coactivator Recruitment at AP-1 Sites by Altered Phosphorylation of both CREB Binding Protein and c-jun

Abstract

Retinoic acid (RA) inhibits matrix metalloproteinase 9 (MMP-9) expression due to AP-1 inhibition resulting from retinoic acid receptors (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. CREB binding protein (CBP) and p300/CBP-associated factor (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 epidermal growth factor had opposing effects on phosphorylation of CBP by extracellular signal-regulated kinase 1 that 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.

Brain-Derived Neurotrophic Factor Induces Matrix Metalloproteinase 9 Expression in Neurons via the Serum Response Factor/c-Fos Pathway

“…In contrast with previous reports showing regulation of MMP-9 expression by CREB and its cofactors in nonneuronal cells (47,48), our data indicate that in neurons BDNF-induced MMP-9 transcription is not mediated by CREB activity. However, as already mentioned, MMP-9 gene expression seems to be modulated in a cell type/stimulus-specific manner.…”

“…As in nonneuronal cells, MMP-9 transcription has been shown to be regulated by another transcription factor, the cAMP response element binding protein (CREB) and its coactivators CREB binding protein (CBP) and p300 (47,48); we verified whether CREB contributes to BDNF-mediated MMP-9 transcription in neurons. We used two different approaches to inhibit endogenous CREB in neurons: we overexpressed inducible cyclic AMP early repressor 2␥ (ICER II␥) (35), which is an endogenous repressor of CREB, or a mutant form of CREB (A-CREB) that inhibits DNA binding of endogenous CREB (34).…”

Cardioprotective effect of miRNA-22 on hypoxia/reoxygenation induced cardiomyocyte injury in neonatal rats

“…CBP as an important transcription co-activator not only regulates transcriptional factor DNA binding, but also can intervene their transcriptional activity (Goodman et al, 2000;Arany et al, 1994). At last, many various transcriptional factors competition for limiting amounts of CBP (Zhao et al, 2011;Ramos et al, 2010;Tsai et al, 2008;Du et al, 2014;Rajendran et al, 2013), which is still an important research problem.…”

“…It functions as a co-activator of DNA binding, regulating the activity of different transcriptional factors, including activator protein-1 (AP-1), nuclear factor kappaB (NF-κB) and CREB (Zhao et al, 2011;Ramos et al, 2010;Tsai et al, 2008;Du et al, 2014). Among these transcriptional factors, AP-1 is known as a key mediator in MI/R injury.…”

Histone Methyltransferase SET1 Mediates Angiotensin II–Induced Endothelin-1 Transcription and Cardiac Hypertrophy in Mice

“…AP-1 is a universally expressed transcription factor known to exert a wide range of effects on the vasculature. 30 Several independent investigations have suggested that AP-1 may enlist the help of epigenetic factors, such as CREB binding protein, 31 PCAF (p300/CBP associated factor), 32 and Brahma-related gene 1, 33 to activate transcription. The finding that AP-1 may rely on SET1-dependent H3K4 methylation to activate endothelin-1 transcription reinforces the assertion that epigenetic factors play essential roles in transcriptional regulation.…”