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Published on: June 21, 2016
RUNX3 regulates the activity of the CD11a and CD49d integrin gene promoters
Angeles Domínguez-Soto1, Miguel Relloso, Miguel A Vega
1Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, Madrid 28020, Spain.
Insights
RUNX3 transcription factor enhances CD49d and CD11a integrin expression, crucial for immune cell migration and T cell activation. This finding reveals RUNX3
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Leukocyte integrins CD11a/CD18 and CD49d are key mediators of immune cell trafficking and T cell activation.
- The CD11a gene promoter's activity relies on MS7 element sequences (RUNX-110, CEBP-100) bound by RUNX and C/EBP transcription factors.
- Differential recognition of MS7 in lymphoid versus myeloid cells and its regulated in vivo occupancy are previously established.
Purpose of the Study:
- To investigate the role of RUNX3 in regulating CD49d gene expression.
- To explore the functional implications of RUNX3-mediated regulation of CD49d and CD11a integrins in dendritic cells.
Main Methods:
- Analysis of gene promoter activity for CD49d.
- Quantitative assessment of mRNA and cell surface integrin expression.
- Correlation studies between RUNX3 mRNA levels and integrin expression in dendritic cells.
Main Results:
- RUNX3 was found to transactivate the CD49d gene promoter.
- Increased CD49d mRNA and integrin expression in mature dendritic cells correlated with elevated RUNX3 mRNA.
- RUNX3's role in regulating both CD11a and CD49d integrins was demonstrated.
Conclusions:
- RUNX3 plays a significant role in upregulating both CD11a and CD49d integrins.
- RUNX3-mediated integrin regulation may enhance dendritic cell functions, including transendothelial migration, antigen presentation, and T cell stimulation.
Abstract:
The leukocyte integrins CD11a/CD18 (LFA-1, alphaLbeta2) and CD49d (VLA-4, alpha4beta1, alpha4beta7) mediate leukocyte transendothelial migration during immune and inflammatory responses and provides co-stimulatory signals for the activation of T lymphocytes. Our previous studies demonstrate that the CD11a gene promoter directs CD11a/CD18 integrin expression, and it depends on two overlapping sequences within the MS7 element, RUNX-110 and CEBP-100, which are recognized by RUNX and C/EBP transcription factor families, respectively. Recognition of MS7 differs in lymphoid (RUNX) and myeloid (C/EBP and RUNX) cells and its in vivo occupancy is regulated in a competitive and differentiation-dependent manner. The functional relevance of these elements are illustrated by the fact that RUNX3 overexpression leads to enhanced CD11a/CD18 levels, whereas RUNX1-ETO-expressing cells exhibit a weak/absent CD11a/CD18 integrin cell surface expression. We now provide evidence that RUNX3 also transactivates the CD49d gene promoter, and that the increased expression of CD49d mRNA and CD49d integrins on mature monocyte-derived dendritic cells correlates with an up-regulation of RUNX3 mRNA. The regulation of CD49d and CD11a integrins by RUNX3 could potentially contribute to the enhancement of transendothelial migration, antigen presentation and T cell stimulatory capabilities of mature dendritic cells.
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