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- Mahameed, M., et al.
(författare)
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The unfolded protein response modulators GSK2606414 and KIRA6 are potent KIT inhibitors
- 2019
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Ingår i: Cell Death and Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- IRE1, PERK, and ATF6 are the three transducers of the mammalian canonical unfolded protein response (UPR). GSK2606414 is a potent inhibitor of PERK, while KIRA6 inhibits the kinase activity of IRE1. Both molecules are frequently used to probe the biological roles of the UPR in mammalian cells. In a direct binding assay, GSK2606414 bound to the cytoplasmic domain of KIT with dissociation constants (K d ) value of 664 ± 294 nM whereas KIRA6 showed a K d value of 10.8 ± 2.9 µM. In silico docking studies confirmed a compact interaction of GSK2606414 and KIRA6 with KIT ATP binding pocket. In cultured cells, GSK2606414 inhibited KIT tyrosine kinase activity at nanomolar concentrations and in a PERK-independent manner. Moreover, in contrast to other KIT inhibitors, GSK2606414 enhanced KIT endocytosis and its lysosomal degradation. Although KIRA6 also inhibited KIT at nanomolar concentrations, it did not prompt KIT degradation, and rescued KIT from GSK2606414-mediated degradation. Consistent with KIT inhibition, nanomolar concentrations of GSK2606414 and KIRA6 were sufficient to induce cell death in a KIT signaling-dependent mast cell leukemia cell line. Our data show for the first time that KIT is a shared target for two seemingly unrelated UPR inhibitors at concentrations that overlap with PERK and IRE1 inhibition. Furthermore, these data underscore discrepancies between in vitro binding measurements of kinase inhibitors and inhibition of the tyrosine kinase receptors in living cells. © 2019, The Author(s).
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- Puram, Sidharth V., et al.
(författare)
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Cellular states are coupled to genomic and viral heterogeneity in HPV-related oropharyngeal carcinoma
- 2023
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:4, s. 640-650
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Tidskriftsartikel (refereegranskat)abstract
- Head and neck squamous cell carcinoma (HNSCC) includes a subset of cancers driven by human papillomavirus (HPV). Here we use single-cell RNA-seq to profile both HPV-positive and HPV-negative oropharyngeal tumors, uncovering a high level of cellular diversity within and between tumors. First, we detect diverse chromosomal aberrations within individual tumors, suggesting genomic instability and enabling the identification of malignant cells even at pathologically negative margins. Second, we uncover diversity with respect to HNSCC subtypes and other cellular states such as the cell cycle, senescence and epithelial-mesenchymal transitions. Third, we find heterogeneity in viral gene expression within HPV-positive tumors. HPV expression is lost or repressed in a subset of cells, which are associated with a decrease in HPV-associated cell cycle phenotypes, decreased response to treatment, increased invasion and poor prognosis. These findings suggest that HPV expression diversity must be considered during diagnosis and treatment of HPV-positive tumors, with important prognostic ramifications.
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- Feldmann, Daneil C., et al.
(författare)
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Investigation of multiple populations highlight VEGFA polymorphisms to modulate anterior cruciate ligament injury
- 2022
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Ingår i: Journal of Orthopaedic Research. - : John Wiley & Sons. - 0736-0266 .- 1554-527X. ; 40:7, s. 1604-1612
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Tidskriftsartikel (refereegranskat)abstract
- Polymorphisms in VEGFA and KDR encoding proteins have been associated with anterior cruciate ligament (ACL) injury risk. We leveraged a collective sample from Sweden, Poland, and Australia to investigate the association of functional polymorphisms in VEGFA and KDR with susceptibility to ACL injury risk. Using a case–control genetic association approach, polymorphisms in VEGFA and KDR were genotyped and haplotypes inferred from 765 controls, and 912 cases clinically diagnosed with ACL rupture. For VEGFA, there was a significant overrepresentation of the rs2010963 CC genotype (p = 0.0001, false discovery rate [FDR]: p = 0.001, odds ratio [OR]: 2.16, 95% confidence interval [CI]: 1.47–3.19) in the combined ACL group (18%) compared to the combined control group (11%). The VEGFA (rs699947 C/A, rs1570360 G/A, rs2010963 G/C) A-A-G haplotype was significantly (p = 0.010, OR: 0.85, 95% CI: 0.69–1.05) underrepresented in the combined ACL group (23%) compared to the combined control group (28%). In addition, the A-G-G construct was significantly (p = 0.036, OR: 0.81, 95% CI: 0.64–1.02) underrepresented in the combined ACL group (12%) compared to the combined CON group (16%). Our findings support the association of the VEGFA rs2010963 CC genotype with increased risk and (ii) the VEGFA A-A-G haplotype with a reduced risk, and are in alignment with the a priori hypothesis. Collectively identifying a genetic interval within VEGFA to be implicated in ACL risk modulation and highlight further the importance of vascular regulation in ligament biology.
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