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Phd Thesis Matthias Scharenberg.Pdf Identification and Characterization of Two Isoforms of Human Megakaryoblastic Leukemia-1 and Their Specific Regulation in Myofibroblast Differentiation Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Matthias Scharenberg aus Haan (Rheinland), Deutschland Basel, 2013 Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch Dieses Werk ist unter dem Vertrag „Creative Commons Namensnennung-Keine kommerzielle Nutzung-Keine Bearbeitung 2.5 Schweiz“ lizenziert. Die vollständige Lizenz kann unter creativecommons.org/licences/by-nc-nd/2.5/ch eingesehen werden. Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. Ruth Chiquet-Ehrismann und Prof. Dr. Gerhard Christofori. Basel, den 18.06.2013 Prof. Dr. Jörg Schibler (Dekan) Namensnennung-Keine kommerzielle Nutzung-Keine Bearbeitung 2.5 Schweiz Sie dürfen: das Werk vervielfältigen, verbreiten und öffentlich zugänglich machen Zu den folgenden Bedingungen: Namensnennung. Sie müssen den Namen des Autors/Rechteinhabers in der von ihm festgelegten Weise nennen (wodurch aber nicht der Eindruck entstehen darf, Sie oder die Nutzung des Werkes durch Sie würden entlohnt). Keine kommerzielle Nutzung. Dieses Werk darf nicht für kommerzielle Zwecke verwendet werden. Keine Bearbeitung. Dieses Werk darf nicht bearbeitet oder in anderer Weise verändert werden. • Im Falle einer Verbreitung müssen Sie anderen die Lizenzbedingungen, unter welche dieses Werk fällt, mitteilen. Am Einfachsten ist es, einen Link auf diese Seite einzubinden. • Jede der vorgenannten Bedingungen kann aufgehoben werden, sofern Sie die Einwilligung des Rechteinhabers dazu erhalten. • Diese Lizenz lässt die Urheberpersönlichkeitsrechte unberührt. Die gesetzlichen Schranken des Urheberrechts bleiben hiervon unberührt. Die Commons Deed ist eine Zusammenfassung des Lizenzvertrags in allgemeinverständlicher Sprache: http://creativecommons.org/licenses/by-nc-nd/2.5/ch/legalcode.de Haftungsausschluss: Die Commons Deed ist kein Lizenzvertrag. Sie ist lediglich ein Referenztext, der den zugrundeliegenden Lizenzvertrag übersichtlich und in allgemeinverständlicher Sprache wiedergibt. Die Deed selbst entfaltet keine juristische Wirkung und erscheint im eigentlichen Lizenzvertrag nicht. Creative Commons ist keine Rechtsanwaltsgesellschaft und leistet keine Rechtsberatung. Die Weitergabe und Verlinkung des Commons Deeds führt zu keinem Mandatsverhältnis. Quelle: http://creativecommons.org/licenses/by-nc-nd/2.5/ch/ Datum: 3.4.2009 Table of Contents Summary.............................................................................................................................................1 Introduction.......................................................................................................................................5 1. Signal transduction - from changes in the cellular microenvironment to changes in gene expression..............................................................................................................6 2. The transcription factor SRF and its regulation by cofactors................................................9 3. The family of myocardin-related transcription factors (MRTF) – transcriptional coactivators of SRF............................................................................................12 4. The Rho-actin-MKL1-SRF pathway - linking the actin cytoskeleton to gene expression.............................................................................................................................14 5. The role of the Rho-actin-MKL1-SRF pathway in embryonic development.........................................................................................................................................19 6. The role of the Rho-actin-MKL1-SRF pathway in physiology and disease....................20 6.1. Involvement in normal mammary gland function and nursing.............................20 6.2. Involvement in megakaryocytic differentiation and leukemia.............................20 6.3. Involvement in progression of solid tumors and their metastasis Review: MegakaryoBlastic leukemia protein-1 (MKL1): Increasing evidence for an involvement in cancer progression and metastasis...............22 6.4. Involvement in myofiBroBlast/cancer-associated fibroblast differentiation - a key player in tissue repair, fibrosis, and cancer .................27 Results...............................................................................................................................................45 Manuscript I: The initial phase of TGF-β-induced myofiBroBlast differentiation involves specific regulation of two MKL1/MRTF-A isoforms...............45 Patent application: Treating diseases By modulating a specific isoform of MKL1…........................................................................................93 Manuscript II: The SRF coregulator MKL1/MRTF-A interacts with pyruvate kinase M1/M2 in proliferating HEK293 cells….......................97 Future Perspectives....................................................................................................................119 Appendix: Additional findings (AF)......................................................................................129 AF I: MKL1_L expression promotes cell migration (preliminary)…..................................130 AF II: Expression of MKL1_S in human Brain tumors seems generally reduced..........134 AF III: Identification of novel MKL1 phosphorylation sites and of MKL1_L-specific phosphorylation..............................................................................138 Acknowledgements....................................................................................................................142 Curriculum Vitae.........................................................................................................................144 Abbreviations ATP/GTP Adenosine/guanosine triphosphate CAF Cancer (carcinoma)-associated fibroblasts ECM Extracellular matrix EMT Epithelial-to-mesenchymal transition EMyT Epithelial-to-myofiBroBlast transition EndMT Endothelial-to-mesenchymal transition FCS Fetal calf serum GEF Guanine nucleotide exchange factor GPCR G protein-coupled receptor hASC Human adipose tissue-derived mesenchymal stem/stromal cell HEK293 Human embryonic kidney cell line 293 LC-MS Liquid chromatography-mass spectrometry LPA Lysophosphatidic acid MAPK Mitogen-activated protein kinase MKL1 MegakaryoBlastic leukemia-1 MMP Matrix metalloproteinase MRTF Myocardin-related transcription factor MSC Multipotent stromal cell/mesenchymal stem cell PKM1/2 Pyruvate kinase isozyme M1/M2 RTK Receptor tyrosine kinase SBE Smad-Binding element SILAC StaBle isotope laBeling with amino acids in cell culture SMA Smooth muscle α-actin SMC Smooth muscle cell SPC Sphingosylphosphorylcholine SRF Serum response factor TAD Transcriptional activation domain TCF Ternary complex factor TGF-β Transforming growth factor-β VSMC Vascular smooth muscle cell Summary Summary 1 Summary Summary The reversible differentiation of various precursor cell types into myofiBroBlasts/cancer-associated fiBroBlasts (CAFs) is an important physiological as well as pathological process. Recently, the Rho-actin-MKL1-SRF pathway has been shown to regulate this process. MKL1 activity has emerged as the crucial relay adjusting the status of the actin cytoskeleton and the transcription of a substantial part of SRF target genes, including smooth muscle-specific genes. To investigate the role of MKL1 in more detail, we analyzed the exact molecular structure of the human MKL1 protein, its gene architecture, and its regulation of expression. For the first time, we descriBe the existence of a second human MKL1 isoform, MKL1_S, that is transcriBed from an alternative promoter. In contrast to the puBlished isoform MKL1_L, expression of this novel isoform varies strongly Between different cell types and tissues. Furthermore, we identified an upstream GTG translation start of MKL1_L, resulting in a long N-terminal tail that is not present in MKL1_S. Using human adipose tissue-derived stem cells (ASCs) as a differentiation model, we were aBle to show that only the shorter isoform MKL1_S is strongly up-regulated within the first 24 h of TGF-β-induced myofiBroBlast/CAF differentiation. TGF-β constitutes the major physiological trigger of the myofiBroBlast/CAF differentiation program. By applying other stimuli that were reported to drive differentiation of MSCs/ASCs into the smooth muscle direction, we found that induction of MKL1_S is specific for TGF-β. To assess the mechanistic role of specific MKL1_S up-regulation, we over-expressed MKL1_S and MKL1_L in HEK293 cells and analyzed target gene expression after stimulation of the Rho-actin-MKL1 pathway. We found that MKL1_S shares the majority of its target genes with MKL1_L, including α- smooth muscle actin. However, we identified several genes that were significantly more strongly induced By MKL1_S, coding for extracellular proteins, such as MMP-16 and SPOCK-3. This MKL1_S-specific activity was mediated By a functional motif in the MKL1_S-specific N-terminal sequence. We postulate that the specific up-regulation of MKL1_S in the initial phase of TGF-β-induced myofiBroBlast/CAF differentiation contributes to the progression to the advanced phase, which is characterized By enhanced contractility, extracellular
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