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Die Enzyme Acyl Protein Thioesterase 1 und 2 (APT1 und APT2) spielen eine wichtige Rolle bei der Depalmitoylierung verschiedener Protein in der Zelle, unter anderem deacylieren sie das Protoonkogen Ras. Damit verhindern sie die fehlerhafte Lokalisierung von Ras an internen Membranen, was die Signalweiterleitung von extraellulären Botenstoffen durch das Ras Protein an der Plasmamembran ermöglicht. Die Repalmitoylierung von Ras erfolgt am Golgi-Apparat. Die Inhibierung von APT kann diesen Zyklu...
Proteins of the Ras family of small GTPases play a major role in the transduction of extracellular signals, especially growth factor signals, into the cell. Ras proteins thereby participate in the regulation of critical processes like cellular growth and proliferation. Due to this central role, gain-of-function mutations of these proteins can have severe consequences for the mutated cells including uncontrolled proliferation and these mutations are often connected to development of diseases i...
The development of novel and efficient methods for the transition metal-free functionalization of inert and abundant C–H bonds offers striking advantages in terms of step- and atom economy under environmentally benign reaction conditions. Metal-free reactions serve as environmentally friendly substitutes for cost intensive and harmful transition metal-catalyzed reactions. However, oxidative coupling reactions under metal-free conditions face some unsolved problems. High molecular weight oxida...
The technological development in analytical methods, especially in chromatography and mass spectrometry, has allowed a deeper understanding of biological systems at a molecular level. Characterization and quantification of biomolecules and its modifications are crucial for comprehension of the entire biological machinery. However, additional bioanalytical methods are needed to gain more detailed information about protein structure, dynamic protein complexes and low abundant protein modificati...
Genetic information within a cell is stored in the nucleotide sequence of deoxyribonucleic acid (DNA). In a multicellular organism, all somatic cells contain the same genetic material i.e. have the same genotype. Nevertheless, they can differ greatly in their morphologies and functions, which is commonly attributed to a differentiated pattern of gene expression. Responsible for the formation of a cell´s specific phenotype are epigenetic modifications, which act as an additional layer of i...
The Hedgehog (Hh) signaling pathway is vital for organ development and tissue patterning during embryogenesis. However, its inappropriate activation is linked to several types of cancers. Therefore, development of small molecule modulators of Hh pathway is of utmost importance in the field of cancer research. A high-throughput cell-based screen in C3H/10T1/2 cells that monitor osteogenesis upon activation of Hh signaling identified YCL-220, RKN-1043 and MJD-1314 as inhibitors of Hh signalin...
The ErbB signaling network comprises a complex dynamic system, which regulates a diverse set of cellular behaviors. In this thesis, we examined how regulating the distribution of ErbB receptors between the plasma membrane and different endosomal compartments enables contextual regulation of receptor activity and signaling. In the first part of this work, we investigated how spatial regulation of EGFR controls its autocatalytic activity. We found that autonomously activated and EGF activated r...
In chemical biology and drug discovery, the development of novel methods for efficient synthesis of structurally distinct molecular scaffolds holds an immense importance. Gold catalyzed enyne cycloisomerizations are a powerful tool to access a wide range of complex molecules owing to the tunable nature of gold complexes with ligand and reaction conditions. A number of reactions have disclosed the role of substrates, ligands of gold(I) catalyst and the nucleophiles to afford a variety of produ...
Nicht-kleinzelliger Lungenkrebs (NSCLC) ist die häufigste Ursache für Krebs-bezogene Todesfälle weltweit.[1] Die Behandlung von NSCLC hat jedoch in den letzten zehn Jahren eine Revolution erfahren: Die Identifizierung von prädiktiven Biomarkern und ein detailliertes Verständnis von deren biochemischen und molekularen Eigenschaften erlaubte die Entwicklung von zielgerichteten, spezifischen Inhibitoren der mutierten Onkoproteine. Diese sogenannte Präzisionsmedizin stellt einen alternativen Beha...
The epidermal growth factor receptor (EGFR), a member of the ErbB family, is a receptor tyrosine kinase that represents a key mediator in critical cellular signaling processes such as cell proliferation, cell cycle regulation as well as apoptosis. Therefore, dysregulation of EGFR plays a pivotal role in the onset and progression of cancer. Mutations in the gene encoding the EGF receptor have been discovered as oncogenic drivers in non-small cell lung cancer (NSCLC). These somatic kinase domai...
Die Verwendung von kleinen organischen Molekülen gegen Rezeptor-Tyrosinkinasen (RTKs) hat sich in der modernen Krebstherapie als wertvolle Therapie-Strategie erwiesen. Die Assoziation von Krebs mit der Dysregulation von Signalwegen, die mit RTKs verbunden sind, ist ein Schlüsselelement in der gezielten Krebstherapie. Die Tyrosinkinase Stammzellenfaktorrezeptor KIT ist ein Beispiel für eine klinisch relevante RTK. KIT ist ein Zielprotein in der Therapie von gastrointestinalen Stroma-tumoren (G...
In dieser Arbeit wurden zwei Strategien zum Aufbau von kompartimentierten GOX/HRP-Reaktionskaskaden untersucht. Die erste Strategie bestand in der Assemblierung der Enzyme im Nanometermaßstab durch Methoden der DNA Nanotechnologie. Hierdurch sollten künstliche Multienzymkomplexe aufgebaut werden, die auf eine mögliche Beschleunigung der Gesamtreaktion durch räumliche Nähe, dem sogenannten „Channeling“, untersucht wurden. Bei der zweiten Strategie wurden die Enzyme in einen Festbettr...
As a major developmental pathway, Hedgehog (Hh) signaling is required for segment polarity in Drosophila and limb pattering in vertebrates. Since its discovery 40 years ago, several studies have identified various pathway components and helped to elucidate the underlying mechanisms of signal transduction. Nevertheless, some regulatory steps during pathway induction are not yet fully understood. Similar to other developmental pathways like Wnt, TGFβ or Notch signaling, also Hh signaling plays ...
Despite having the same "purpose", the uncontrollable cellular growth to the detriment of the organism, cancer presents itself in humans in great variety of forms. This variety makes developing effective treatments a highly challenging task. Nevertheless, cancer has a handful of hallmarks that are present almost ubiquitously in all types of tumours. Among them is the upregulated glucose uptake, known as the Warburg effect. However, there has yet to be a drug or treatment that makes use of thi...
In mammals, DNA methylation is an epigenetic modification and the most widely characterized epigenetic nucleobase is 5-methylcytosine (5mC), that causes downregulation of gene transcription. Several studies have shown a direct link between the presence of 5mC in promoters of tumour suppressor genes and various cancers, autoimmune diseases, metabolic disorders and neurodegenerative ailments such as Schizophrenia, Fragile X and Prader-Willi syndrome. This thesis was focussed on the developmen...
The main function of protein kinases is widely considered the activation of their substrates by catalytic phosphotransfer from adenosine-5‘-triphosphate (ATP), explaining the central role of kinases in cellular signaling cascades. Recently, more and more functions independent from this catalytic mechanism were described, that are involved in several biological processes, e.g., by regulation or localization of their substrates via protein-protein interactions or the formation of multi-enzyme c...