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New aspects of pregnane X receptor function and regulation
Hyršová, Lucie ; Trejtnar, František (advisor) ; Skálová, Lenka (referee) ; Vondráček, Jan (referee)
Charles University, Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Candidate: Lucie Hyršová, MSc. First Supervisor: doc. PharmDr. František Trejtnar, CSc. Consultant: prof. PharmDr. Petr Pávek, PhD. Title of Dissertation Thesis: New aspects of pregnane X receptor function and regulation The pregnane X receptor belongs to the superfamily of nuclear receptors; it is a ligand dependent transcription factor regulating expression of its target genes. During last two decades, PXR was extensively studied as a xenosensor, i.e. the receptor, which is able to bind xenobiotics including many drugs and to regulate their metabolism by induction of the most important metabolizing enzymes of both phase I. and phase II. Induction, i.e. transcriptional stimulation of expression of the most important cytochrome P450 enzymes, by PXR ligands was described in details at many levels. Within this dissertation thesis, I am dealing with aspects of regulation via PXR, which extend the common understanding of PXR as a receptor whose exclusive function is to up-regulate drug metabolizing enzymes mediated by its agonists. Within the first, project I studied regulation of OCT1 transporter in hepatic cell models, I shown that PXR did not induce, but it rather suppressed the expression of this...
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Canonical and non-canonical signalling triggered by activated TRAIL receptors in human cells
Nahácka, Zuzana ; Anděra, Ladislav (advisor) ; Rudolf, Emil (referee) ; Vondráček, Jan (referee)
TRAIL ligand can trigger apoptosis of permissive human cells via engagement of its two pro- apoptotic receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). Its ability to induce apoptosis independently on p53 status and to selectively kill cancer cells in vitro and in vivo made this ligand an attractive target in cancer research. However, acquired resistance of primary cancer cells, unsatisfactory outcome of clinical trials and recent studies arguing that TRAIL might under specific conditions promote cancer progression, opened new plethora of questions, which need to be addressed. Though both receptors DR4 and DR5 are ubiquitously expressed, different types of tumours show preference for either of the receptors. The relative participation of DR4 and DR5 in TRAIL- induced signalling is still largely unknown. To analyse TRAIL receptor-specific signalling, I prepared Strep-tagged, trimerised variants of recombinant human TRAIL ligands with high affinity for either DR4 or DR5 receptor. Using these receptor-specific ligands, I examined a contribution of individual pro-apoptotic receptors to TRAIL-induced signalling pathways. I found that in TRAIL resistant colorectal HT-29 cells but not in pancreatic PANC-1 cancer cells, DISC formation and initial caspase-8 processing proceeded comparably in both DR4- and...
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