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Dissecting the ß-Catenin-Dependent and -Independent Functions of BCL9 and BCL9-2 in Intestinal Tumorigenesis

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Dissecting the ß-Catenin-Dependent and -Independent Functions of BCL9 and BCL9-2 in Intestinal Tumorigenesis Dissecting the ß-catenin-dependent and -independent functions of BCL9 and BCL9-2 in intestinal tumorigenesis Doctoral Thesis In partial fulfillment of the requirements for the degree “Doctor rerum naturalium (Dr. rer. nat.)” in the Molecular Medicine Study Program at the Georg-August University Göttingen submitted by Maria Wiese from Halberstadt, Germany Göttingen, December 2012 Members of the Thesis Committee Supervisor Prof. Dr. Felix H. Brembeck Hematology/Oncology/Tumor Biology and Signal Transduction University Medical Center Göttingen Second Member of the Thesis Committee Prof. Dr. Matthias Dobbelstein Molecular Oncology University Medical Center Göttingen Third Member of the Thesis Committee Prof. Dr. Uwe-Karsten Hanisch Neuropathology University Medical Center Göttingen Date of Disputation: AFFIDAVIT Here I declare that my doctoral thesis entitled “Dissecting the ß-catenin-dependent and -independent functions of BCL9 and BCL9-2 in intestinal tumorigenesis” has been written independently with no other sources and aids than quoted. Göttingen, 17.12.12 (Maria Wiese) TABLE OF CONTENTS Table of Contents Zusammenfassung ................................................................................................... V Abstract ................................................................................................................. VII List of Figures ....................................................................................................... VIII List of Tables ............................................................................................................. X Abbreviations .......................................................................................................... XI 1 Introduction ........................................................................................................... 1 1.1 The Wnt/ß-catenin-signaling pathway in intestinal development, homeostasis and tumorigenesis ............................................................................................................................1 1.1.1 The role of ß-catenin in canonical Wnt-signaling .........................................................1 1.1.2 The Wnt/ß-catenin signaling pathway in intestinal development ...............................3 1.1.3 The Wnt/ß-catenin-signaling pathway and ß-catenin target genes in intestinal homeostasis and tumorigenesis ............................................................................................4 1.2 The BCL9 proteins ................................................................................................................7 1.2.1 BCL9 and BCL9-2 encode the vertebrate orthologs of Drosophila Legless ...................7 1.2.2 The BCL9/Legless proteins are co-factors of the Wnt/ß-catenin signaling pathway ....8 1.2.3 BCL9 proteins in development, regeneration and tumorigenesis ................................9 1.3. K19 dependent BCL9-2 overexpression in vivo ................................................................ 11 1.4. Transcriptional regulatory mechanisms .......................................................................... 12 1.4.1 Basal transcriptional regulatory mechanisms ............................................................ 12 1.4.2 Mechanisms of ß-catenin dependent transcriptional regulation of Wnt/ß-catenin target genes ........................................................................................................................ 15 1.4.3. Crosstalk of LEF/TCF and SP1 in the transcriptional control of target gene expression ............................................................................................................................................ 17 1.4.4 Transcriptional regulatory mechanism of Wnt/ß-catenin target genes by the BCL9 and Pygopus co-factors ....................................................................................................... 18 2 Aim of this work .................................................................................................. 20 3 Materials and Methods ........................................................................................ 21 3.1 General materials and chemicals ...................................................................................... 21 3.2 Oligonucleotides and siRNA .............................................................................................. 30 3.3 Cell biology ........................................................................................................................ 36 3.3.1 Bacterial strains .......................................................................................................... 36 3.3.2 Cell lines and mouse strains ....................................................................................... 36 3.4 Plasmids ............................................................................................................................ 38 I TABLE OF CONTENTS 3.5 Buffers and solutions ........................................................................................................ 39 3.5 Software ............................................................................................................................ 55 3.6 Microbiology ..................................................................................................................... 40 3.6.1 Cultivation and storage of E. coli ............................................................................... 40 3.6.2 Generation of chemo-competent E. coli .................................................................... 40 3.6.2 Transformation of E. coli ............................................................................................ 40 3.7 Molecular biology ............................................................................................................. 41 3.7.1 Isolation of nucleic acids ............................................................................................ 41 3.7.2 Purification and extraction of nucleic acids ............................................................... 42 2.7.3 Amplification of nucleic acids .................................................................................... 42 3.7.4 Molecular cloning....................................................................................................... 45 3.7.5 Microarray analysis .................................................................................................... 46 3.8 Biochemistry ..................................................................................................................... 47 3.8.1 Isolation of proteins from cell cultures ...................................................................... 47 3.8.2 SDS-PAGE and Western Blot ...................................................................................... 48 3.8.3 Immunoprecipitation ................................................................................................. 49 3.8.4 Luciferase assays ........................................................................................................ 50 3.9 In vivo model systems ....................................................................................................... 50 3.9.1 Mouse model systems ............................................................................................... 50 3.9.2 Tissue processing for immunohistochemistry and Immunofluorescence ................. 51 3.9.3 Immunostaining of tissues ......................................................................................... 51 3.9.4 Scoring of human tissue microarray .......................................................................... 53 3.9.5 Cell culture model systems ........................................................................................ 53 3.10 Statistics .......................................................................................................................... 55 4 Results ................................................................................................................. 56 4.1 BCL9 and BCL9-2 expression in normal intestine and during intestinal tumorigenesis ... 56 4.1.1 BCL9-2 expression is restricted to the villi of the normal intestine and is up-regulated in early stages of intestinal tumorigenesis ......................................................................... 56 4.1.2 BCL9-2, but not BCL9, is highly expressed in human colon cancers .......................... 57 4.2 BCL9-2 overexpression promotes intestinal tumor development .................................... 59 4.2.1 BCL9-2 expression in compound APCMin/+; K19-BCL9-2 transgenic mice ................... 59 4.2.2 BCL9-2 overexpression promotes tumor formation and local invasion .................... 61 4.3 BCL9 and BCL9-2 protein expression in colon cancer cell lines ........................................ 63 4.4 Analysis of the dependency of the transcriptional control of ß-catenin, BCL9 and BCL9-2 on RNA Interference ............................................................................................................... 64 II TABLE OF CONTENTS 4.5 BCL9 and BCL9-2 knockdown reverts the mesenchymal malignant phenotype of cancer cell lines ................................................................................................................................... 66 4.6 BCL9 and BCL9-2 are not target genes of ß-catenin ........................................................
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