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Dissertation Philip Böhler Three Tales of Death: New Pathways in the Induction, Inhibition and Execution of Apoptosis Inaugural-Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf vorgelegt von Philip Böhler aus Bonn Düsseldorf, Juni 2019 aus dem Institut für Molekulare Medizin I der Heinrich-Heine-Universität Düsseldorf Gedruckt mit der Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf Berichterstatter: 1. Prof. Dr. Sebastian Wesselborg 2. Prof. Dr. Henrike Heise Tag der mündlichen Prüfung: 29. Oktober 2019 “Where the first primal cell was, there was I also. Where man is, there am I. When the last life crawls under freezing stars, there will I be.” — DEATH, in: Mort, by Terry Pratchett “Right away I found out something about biology: it was very easy to find a question that was very interesting, and that nobody knew the answer to.” — Richard Feynman, in: Surely You're Joking, Mr. Feynman! Acknowledgements (Danksagung) Acknowledgements (Danksagung) Viele Menschen haben zum Gelingen meiner Forschungsarbeit und dieser Dissertation beigetragen, und nicht alle können hier namentlich erwähnt werden. Dennoch möchte ich einige besonders hervorheben. An erster Stelle möchte ich Professor Sebastian Wesselborg danken, der diese Dissertation als Erstgutachter betreut hat und der mir die Möglichkeit gab, die dazugehörigen experimentellen Arbeiten am Institut für Molekulare Medizin durchzuführen. Er und Professor Björn Stork, dem ich für die herzliche Aufnahme in seine Arbeitsgruppe danke, legten durch die richtige Mischung aus aktiver Förderung und dem Freiraum zur Umsetzung eigener wissenschaftlicher Ideen die ideale Grundlage für die Forschungsprojekte, aus denen diese Dissertation entstand. Professorin Henrike Heise, die sich freundlicherweise zur Betreuung dieser Dissertation als Zweitgutachterin bereiterklärt hat, gilt ebenfalls mein herzlicher Dank. Allen Mitgliedern des Instituts für Molekulare Medizin und des Instituts für Molekulare Radioonkologie danke ich für die schöne gemeinsame Zeit nicht nur im Labor. Ich freue mich, dass hieraus auch viele persönliche Freundschaften erwachsen sind. Professor Peter Proksch und seiner Arbeitsgruppe, insbesondere Marian Frank und Hendrik Niemann, danke ich für ihren Anstoß des Phomoxanthon-Projekts und für ihre Beiträge dazu, sowie für die unermüdliche Bereitstellung immer neuer Chargen für unsere Experimente. I would also like to express my thanks to Professor Andreas Reichert and his research group, especially to Ruchika Anand and Arun Kondadi, for their invaluable support with the experiments on mitochondria. Professor Hans Reinke und Gabi Schoder danke ich für ihre wertvollen Beiträge zum BMAL1-Projekt. Ein großer Dank gilt meinen Eltern, die schon in frühen Jahren meine Neugier und meinen Forschergeist unterstützt und gefördert haben und die mir in allen Lebenslagen stets zur Seite standen. Zu guter Letzt und ganz besonders danke ich Marta. Unsere gemeinsamen Stunden am Durchflusszytometer waren der Beginn von mehr als nur einer wunderbaren Freundschaft. Ich bin glücklich und dankbar, dass Du mein Leben bereicherst. iv Summary Summary Death is not always a matter of accident. In many multicellular lifeforms including humans, the death of cells that have become unnecessary or even dangerous to the organism takes place through a regulated process termed apoptosis. This dissertation is based on three research projects that contributed to the understanding of three aspects of apoptosis: its induction, inhibition and execution (Figure 1). To tell these “three tales of death” in the proper context, the reader is provided with a short introduction to apoptosis with a focus on those aspects. The first project investigated the induction of apoptosis by the mycotoxin phomoxanthone A (PXA). It was shown that this small molecule targets the mitochondria and disrupts their form and function in multiple ways: it elicits a strong mitochondrial release of Ca2+, depolarises the mitochondria, inhibits the respiratory chain, and rapidly collapses the mitochondrial network into fragments. Cytochrome c, which is normally a component of the respiratory chain, is released from these damaged mitochondria and triggers the assembly of the apoptosome, thus leading to apoptosis. In the second project, a new regulatory feature was identified in the PI3K/PDK1/AKT signalling pathway that contributes to the inhibition of apoptosis. Through the newly found feedback loop in this pathway, inhibition or genetic deletion of AKT or PDK1 leads to an increase in PI3K expression that depends on the transcription factor FOXO1. The third project was concerned with the execution of apoptosis. During this final phase of the process, the cell and its components are disassembled and prepared for disposal and recycling. The transcription factor BMAL1, which is a component of the circadian clock that regulates day/night cycles in healthy cells, was characterised as one of the cellular components that are specifically targeted and degraded by the effectors of apoptosis. Through this mechanism, apoptosis inactivates the cellular circadian clock. Taken together, the findings of these three research projects and the corresponding publications may have implications for basic research on mitochondrial morphology and the circadian clock, and for clinical research on anticancer regimens that target the PI3K/PDK1/AKT pathway to induce cancer cell apoptosis. v Summary Figure 1: Graphical summary. Apoptosis can be triggered by many stimuli including the mycotoxin phomoxanthone A (PXA; green panel). While PXA damages the mitochondria directly, induction of apoptosis almost always involves mitochondrial outer membrane permeabilization (MOMP) via recruitment of BAX and its association with BAK to form pores that allow the release of cytochrome c (CYCS). Release of CYCS results in assembly of the apoptosome, which activates the initiator caspase CASP9. This is prevented by the pathways of the inhibition of apoptosis, which include PI3K/PDK1/AKT signalling (blue panel). Initiation of this pathway can be caused by the binding of growth factors (GF) to growth factor receptors (GFR), resulting in the conversion of PIP2 into PIP3 by class 1 PI3K. Inactive AKT as well as PDK1 are recruited to PIP3, and AKT is activated via phosphorylation by PDK1 and mTORC2. Active AKT inhibits MOMP and CASP9, and it also negatively regulates itself via a feedback loop involving FOXO1. If the signals in favour of initiation of apoptosis exceed those in favour of inhibition of apoptosis, the cell enters the phase of the execution of apoptosis (red panel). In this phase, executioner caspases such as CASP3 facilitate the controlled demolition of the cell by cleaving various substrate proteins. These include the transcription factor BMAL1, whose transactivation domain (TAD) is cleaved off by CASP3. This renders BMAL1 unable to recruit the coactivators CBP and P300 and thus disables BMAL1-regulated gene transcription. vi Summary in German (Zusammenfassung) Summary in German (Zusammenfassung) Der Tod ist nicht immer eine Frage des Zufalls. In vielen mehrzelligen Lebewesen einschließlich des Menschen erfolgt der Tod einzelner Zellen, die für den Organismus unnötig oder gar gefährlich geworden sind, durch eine sorgfältig regulierte Form des Zelltodes, die als Apoptose bezeichnet wird. Die vorliegende Arbeit basiert auf drei Forschungsprojekten, die verschiedene Aspekte der Apoptose untersuchten: ihre Einleitung (Induktion), ihre Hemmung (Inhibition) und ihre Ausführung (Exekution). Zudem beinhaltet die Arbeit eine umfassende Einleitung mit Schwerpunkten auf diesen drei Aspekten. Das erste Forschungsprojekt untersuchte die Induktion der Apoptose durch das Mykotoxin Phomoxanthon A (PXA). Es wurde gezeigt, dass PXA die Form und Funktion der Mitochondrien in vielfältiger Weise beeinträchtigt: es setzt mitochondriales Ca2+ frei, depolarisiert die Mitochondrien, inhibiert die Atmungskette und führt zum Zusammenbruch der mitochondrialen Netzwerkstruktur. Dadurch kommt es zu einer Freisetzung mitochondrialer Bestandteile einschließlich Cytochrom c ins Zytoplasma, wodurch in betroffenen Zellen Apoptose induziert wird. Im Rahmen des zweiten Forschungsprojekts wurde eine neue regulatorische Komponente des PI3K/PDK1/AKT-Signalwegs identifiziert, der zur Inhibition der Apoptose beiträgt und somit bei Dysregulation ein hohes onkogenes Potenzial birgt. Mehrere experimentelle Krebsmedikamente sind daher gegen Komponenten dieses Signalwegs gerichtet. Eine Inhibition von AKT führt jedoch über eine durch FOXO1-vermittelte Rückkopplung zu einer verstärkten Expression von PI3K. Das dritte Forschungsprojekt beschäftigte sich mit der finalen Phase der Apoptose, während der die Zelle und ihre Komponenten systematisch abgebaut werden. Die Ergebnisse dieses Projekts demonstrieren, dass die Effektoren der Apoptose sich hierbei auch gezielt gegen den Transkriptionsfaktor BMAL1 richten, welcher in gesunden Zellen ein Bestandteil der zirkadianen Uhr der Zelle ist. Die Apoptose inaktiviert damit die zelluläre innere Uhr. Im Anschluss an die fachliche Einleitung, die Übersicht über die drei Forschungsprojekte und die daraus hervorgegangenen Fachpublikationen folgt eine Diskussion deren möglicher Bedeutung für die Grundlagenforschung zu mitochondrialer Morphologie, zur inneren Uhr und zur Apoptose sowie für die klinische Forschung zu PI3K/PDK1/AKT-Inhibitoren in der Krebstherapie. vii Table of
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