| 1. |
- Fernandes, Ricardo A., et al.
(författare)
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A cell topography-based mechanism for ligand discrimination by the T cell receptor
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 116:28, s. 14002-14010
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Tidskriftsartikel (refereegranskat)abstract
- The T cell receptor (TCR) initiates the elimination of pathogens and tumors by T cells. To avoid damage to the host, the receptor must be capable of discriminating between wild-type and mutated self and nonself peptide ligands presented by host cells. Exactly how the TCR does this is unknown. In resting T cells, the TCR is largely unphosphorylated due to the dominance of phosphatases over the kinases expressed at the cell surface. However, when agonist peptides are presented to the TCR by major histocompatibility complex proteins expressed by antigen-presenting cells (APCs), very fast receptor triggering, i.e., TCR phosphorylation, occurs. Recent work suggests that this depends on the local exclusion of the phosphatases from regions of contact of the T cells with the APCs. Here, we developed and tested a quantitative treatment of receptor triggering reliant only on TCR dwell time in phosphatase-depleted cell contacts constrained in area by cell topography. Using the model and experimentally derived parameters, we found that ligand discrimination likely depends crucially on individual contacts being ∼200 nm in radius, matching the dimensions of the surface protrusions used by T cells to interrogate their targets. The model not only correctly predicted the relative signaling potencies of known agonists and nonagonists but also achieved this in the absence of kinetic proofreading. Our work provides a simple, quantitative, and predictive molecular framework for understanding why TCR triggering is so selective and fast and reveals that, for some receptors, cell topography likely influences signaling outcomes.
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| 2. |
- Yang, L., et al.
(författare)
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Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell-fibronectinadhesion of colon cancer cells
- 2010
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Ingår i: Oncogene. - : Nature publishing group. - 0950-9232 .- 1476-5594. ; 29:4, s. 516-526
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Tidskriftsartikel (refereegranskat)abstract
- The role of peroxisome proliferator-activated receptor-/ (PPAR-/) in the pathogenesis of colon cancer remains highly controversial. This study specifically silenced the PPAR- expression in three colon cancer cell lines with different metastatic potentials. Although PPAR-knockdown resulted in more malignant morphological changes, bigger colony sizes and lower carcinoembryonic antigen (CEA) secretion, and enhanced the cell-fibronectin adhesion, cell invasion and migration were unaffected. These effects were stronger in poorly metastatic cell lines compared with highly metastatic ones. Simultaneously, PPAR-knockdown decreased the mRNAs encoding adipocyte differentiation-related protein and liver fatty acid binding protein, and increased the mRNA of ILK, whereas the mRNAs encoding integrin-1 and angiopoietin-like 4 were unchanged. Using immunohistochemistry, we determined that the intensity of PPAR- expression was stronger in rectal cancers with better differentiation than in those with poor differentiation, and was stronger in early-stage tumors than in advanced ones. Together, these findings consistently indicate that PPAR- may facilitate differentiation and inhibit the cell-fibronectin adhesion of colon cancer, having a role as an inhibitor in the carcinogenesis and progression of colorectal cancer. Interestingly PPAR- seems to have a more important role in poorly metastatic cells than in highly metastatic ones.
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