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Oligopeptide Competition Assay for Phosphorylation Site Determination
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Extracellular signals regulate rapid coactivator recruitment at AP-1 sites by altered phosphorylation of both CREB

Linh N Tsai1, Tony K S Ku, Nader K Salib

  • 1University of Illinois Cancer Center, 801 S. Paulina Street, Room 530C, MC860, Chicago, IL 60612, USA.

Molecular and Cellular Biology
|April 30, 2008
PubMed

Insights

Retinoic acid rapidly regulates MMP-9 expression by influencing coactivator protein phosphorylation and exchange at AP-1 sites, a process mediated by protein kinases.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Gene Regulation

Background:

  • Retinoic acid (RA) inhibits matrix metalloproteinase 9 (MMP-9) via AP-1 inhibition, but rapid transcription kinetics suggest active regulation.
  • Previous studies indicated that coactivator and transcription factor phosphorylation might rapidly regulate MMP-9 expression.

Purpose of the Study:

  • To investigate the role of coactivator and transcription factor phosphorylation in the rapid regulation of MMP-9 expression by RA.
  • To elucidate the mechanisms of extracellular signal-mediated coactivator exchange at AP-1 sites.

Main Methods:

  • Investigated the displacement of CREB binding protein (CBP) and p300/CBP-associated factor (PCAF) from the MMP-9 promoter upon RA treatment.
  • Analyzed the effects of RA and epidermal growth factor on CBP phosphorylation by extracellular signal-regulated kinase 1 (ERK1).
  • Identified and characterized a novel phosphorylation site in CBP and its role in AP-1 site association.

Main Results:

  • RA treatment rapidly displaced CBP and PCAF from MMP-9 promoter AP-1 sites.
  • RA and EGF had opposing effects on CBP phosphorylation by ERK1, correlating with altered CBP occupancy and MMP-9 promoter activation.
  • A novel CBP phosphorylation site mediated association with AP-1 sites, and c-jun phosphorylation was crucial for PCAF recruitment and promoter activity.

Conclusions:

  • Extracellular signals rapidly regulate MMP-9 expression through phosphorylation-dependent coactivator exchange at AP-1 sites.
  • Protein kinase pathways mediate coactivator exchange, involving novel interactions between coactivators and AP-1 proteins.

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