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CUX1 transcription factor is a downstream effector of the proteinase-activated receptor 2 (PAR2)

Brian J Wilson1, Ryoko Harada1, Lam LeDuy1

  • 1Goodman Cancer Centre, McGill University, Montreal, Quebec H3A 1A3, the Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, and the Departments of Biochemistry, Medicine, and Oncology, McGill University, Montreal, Quebec H3A 1A3, Canada.

The Journal of Biological Chemistry
|October 28, 2008
PubMed

Insights

Proteinase-activated receptor 2 (PAR2) signaling activates the CUX1 homeodomain protein, a key transcription factor. This activation leads to increased expression of genes involved in inflammation and cell processes.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • G-protein coupled receptor signaling

Background:

  • Proteinase-activated receptors (PARs) are GPCRs involved in cellular processes like inflammation.
  • Mechanisms linking PARs to transcriptional changes remain largely unknown.

Purpose of the Study:

  • To investigate the downstream transcriptional effectors of PAR2 signaling.
  • To identify the role of CUX1 homeodomain protein in PAR2-mediated transcriptional regulation.

Main Methods:

  • Stimulation of epithelial and fibroblastic cells with trypsin or PAR2-activating peptide (PAR2-AP).
  • Assessing CUX1 DNA binding activity using recombinant CUX1 proteins.
  • Gene expression analysis in cux1(-/-) mouse embryo fibroblasts.
  • Reporter assays and gene activation studies in infected cells.
  • Analysis of CUX1 recruitment to gene promoters in breast tumor cells.

Main Results:

  • PAR2 activation by trypsin or PAR2-AP rapidly increased CUX1 DNA binding activity in a PAR2-specific manner.
  • CUX1 DNA binding domains (CR3 and homeodomain) are crucial for this regulation.
  • Three genes—interleukin-1alpha, matrix metalloproteinase-10, and cyclo-oxygenase-2—were identified as downstream targets of both PAR2 and CUX1.
  • p110 CUX1 activated these target genes in reporter assays and upon cell infection.
  • PAR2 activation led to CUX1 recruitment to target gene promoters and increased mRNA levels.

Conclusions:

  • CUX1 is a downstream effector of PAR2 signaling.
  • PAR2 activation triggers a cascade leading to CUX1 stimulation and transcriptional activation of target genes.
  • This pathway links PAR2 to the regulation of inflammatory and matrix-degrading genes.

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