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• W1586244927 abstract "One of the hallmarks of a living organism is the ability to respond to intra- orextracellular changes. These responses involve panoply of enzymes mediating signalsthrough the cell and regulating distinct cellular functions. Protein kinases and proteinphosphatases are important antagonists in this finely balanced process. Protein phosphatase 2A (PP2A) is one of the major serine/threonine-specificphosphatases and has the most diverse substrate specificity of all protein serine/threoninephosphatases in the cell. PP2A consists of a core dimer made up of the 36-kDa catalyticsubunit C tightly complexed with the scaffold regulatory subunit PR65/A. This complexassociates with any one of the second or variable regulatory subunits PR55/B, PR61/B’,PR72/B” or PR110/B’’’ to form an extensive array of trimeric holoenzymes. PP2Aimpacts on all major signaling pathways by reversing the functions of protein kinases andis, therefore, considered to be a central regulator of eucaryotic signal transduction.Dysfunction of this molecule may have severe consequences for the organism and it is,therefore, not surprising that PP2A has become an important target in the investigation ofvarious diseases. We investigated the function of invariant active-site residues of PP2A that are crucial forcatalytic function of the enzyme. A baculovirus system using High Five insect cells wasdeveloped that allowed high level expression of active PP2A which was used forstructural and functional analysis. Site-directed mutagenesis of PP2Ac and purification ofmutant proteins from insect cells combined with functional analysis in yeast provided apowerful system for structure–function analysis of PP2Ac. Mutation of the active-siteresidues Asp88 or His118 within the human PP2A catalytic α subunit impaired catalyticactivity in vitro and in vivo indicating an important role for these residues in catalysis. As PP2A containing the PR55/B regulatory subunit is known to be involved in thepathogenesis of neurodegenerative disorders, we characterized the PR55/B family withparticular emphasis on its distribution and developmental regulation in the brain. The study revealed new aspects of genomic organization and variability, as well as hithertounknown expression patterns of the PR55/B family in the brain. We also found distinctsubcellular localizations of PR55/B isoforms in areas of the brain known to be affectedby Alzheimer’s disease. In addition, our results suggest a distinct role for PR55/Bα inastrocytosis, given that this isoform is highly expressed in activated astrocytes.Interestingly, astrocyte activation is an early step in the pathogenesis of Alzheimer’sdisease and related disorders. In addition, we attempted to define the transcriptional effects of the PP2A-inhibitorokadaic acid (OA) on promoter complexes using Affymetrix GeneChips. Based onknown target genes and further target genes that we identified, we suggest that OAmainly stimulates transcription activators and/or inhibits transcription repressors,probably by inhibition of PP2A. In order to investigate genes that are transcriptionally coregulatedby OA, we developed a software tool we named “StampCollector” that predictspotential transcription factor pairs (TF pairs) involved in the regulation of genes based ontheir promoter sequences. Taken together, the results presented in this thesis underline the significance of PP2A inthe regulation of cellular events. We combined various approaches in order tocharacterize the precise role of PP2A and its PR55/B regulatory subunits in generegulation. Considering the putative role of PP2A in the pathogenesis of human disease,our results may lead eventually to the discovery of therapeutic agents for specificallycounteracting PP2A dysfunction." @default.
• W1586244927 created "2016-06-24" @default.
• W1586244927 creator A5011354281 @default.
• W1586244927 date "2004-01-01" @default.
• W1586244927 modified "2023-09-25" @default.
• W1586244927 title "Analysis of the structure and function of protein phosphatase 2A" @default.
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