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University of California, San Diego UNIVERSITY OF CALIFORNIA, SAN DIEGO Elucidating the Functions and Signaling Mechanisms of the Chemokine CXCL12 and Its Receptors CXCR4 and CXCR7 in Cancer A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences by Morgan L. O’Hayre Committee in charge: Professor Tracy Handel, Chair Professor Anthony Hunter Professor Elizabeth Komives Professor Alexandra Newton Professor Jing Yang 2011 Copyright Morgan L. O’Hayre, 2011 All rights reserved. This dissertation of Morgan L. O’Hayre is approved, and it is acceptable in quality and form for publication on microfilm and electronically: ________________________________________________________ ________________________________________________________ ________________________________________________________ ________________________________________________________ ________________________________________________________ Chair University of California, San Diego 2011 iii DEDICATION I dedicate this dissertation to my Grandma Lucy, who continues to be an inspiration and encouragement for me even though she is no longer with us. iv EPIGRAPH A system maintains a certain fluid stability that can be destroyed by a misstep in just one niche Frank Herbert v TABLE OF CONTENTS Signature Page .................................................................................................................iii Dedication ........................................................................................................................ iv Epigraph............................................................................................................................ v Table of Contents............................................................................................................. vi List of Abbreviations........................................................................................................xiv List of Figures..................................................................................................................xvi List of Tables.................................................................................................................xxiii Acknowledgements .......................................................................................................xxiv Curriculum Vitae.......................................................................................................... xxviii Abstract of the Dissertation ...........................................................................................xxxi CHAPTER 1 Introduction to Chemokines ..................................................................... 1 1.1 General Introduction to Chemokines and Chemokine Receptors ................... 1 1.2 Diversity and Signaling Complexity in the Chemokine Network...................... 4 Functional Selectivity/Ligand Bias of Chemokines and Implications on Design of Therapeutic Agents ................................................................... 7 1.3 Chemokines Receptor Oligomerization and Crosstalk.................................. 14 1.4 Chemokine Involvement in Disease and Cancer........................................... 21 Chemokines in Cancer ............................................................................ 22 Chemokines in Metastasis....................................................................... 23 Chemokines in the Tumor Microenvironment .......................................... 26 1.5 Interplay between CXCL12, CXCR4 and CXCR7 ......................................... 30 vi 1.6 Synopsis of the Dissertation.......................................................................... 37 Acknowledgements ............................................................................................. 40 References .......................................................................................................... 41 CHAPTER 2 Targeted Investigation of CXCL12/CXCR4 Signaling in Chronic Lymphocytic Leukemia ................................................................................................ 58 2.1 Introduction to B cell Chronic Lymphocytic Leukemia................................... 58 2.2 Expression and Purification of CXCL12 ........................................................ 67 2.3 Characterization of CXCL12-mediated Survival in Aggressive (ZAP-70+) Versus Indolent (ZAP-70-) CLL ........................................................................... 71 2.4 Elucidation of CXCL12-Induced Signaling Downstream of Akt ..................... 75 2.5 Characterization of CXCL12-Meidated MDM2 Phosphorylation ................... 78 2.6 2-Dimensional Gel Electrophoresis (2DE) Imaging of Unstimulated and CXCL12-Stimulated CLL Cells ............................................................................ 87 2.7 Summary ....................................................................................................... 89 2.8 Materials and Methods .................................................................................. 91 Acknowledgements ............................................................................................. 96 References .......................................................................................................... 97 CHAPTER 3 Chronic Lymphocytic Leukemia Cells Receive Raf-Dependent Survival Signals in Response to CXCL12 that Are Sensitive to Inhibition by Sorafenib. Messmer D et al. (2011) Blood 117(3): 882-9.......................................... 102 Abstract ............................................................................................................. 103 Introduction........................................................................................................ 103 Methods............................................................................................................. 103 vii Results .............................................................................................................. 105 Influence of CXCL12 on calcium flux and receptor turnover in ZAP-70+ CLL cells versus ZAP-70- CLL cells ...................................................... 105 Intracellular signaling in response to CXCL12....................................... 105 CXCL12-mediated MEK activation in ZAP-70+ CLL cells is RAF dependent.............................................................................................. 106 Sorafenib causes enhanced apoptosis in ZAP-70+ CLL cells............... 107 Sorafenib causes apopotosis of CLL cells in the presence of NLCs ..... 107 Discussion ......................................................................................................... 108 Acknowledgements ........................................................................................... 109 Authorship ......................................................................................................... 109 References ........................................................................................................ 109 Supplemental Information ................................................................................. 111 Acknowledgements ........................................................................................... 117 CHAPTER 4 Mechanisms and Consequences of the Loss of PHLPP1 Phosphatase in Chronic Lymphocytic Leukemia............................................................................ 118 4.1 Abstract ....................................................................................................... 118 4.2 Introduction.................................................................................................. 119 4.3 Results ........................................................................................................ 121 4.3.1 PHLPP1 Protein is Absent in >90% of Patients’ CLL Cells .......... 121 4.3.2 Loss of PHLPP1 Protein Expression Corresponds with a Decrease in mRNA Expression.............................................................................. 123 4.3.3 Expression of PHLPP1 in CLL Cells Decreases Their Signaling Response to CXCL12............................................................................ 127 viii 4.3.4 Sequencing for Potential Mutations in the PHLPP1 Gene............ 131 4.3.5 CLL B Cells Exhibit Higher Levels of PHLPP1 Gene Methylation Compared to B cells from Healthy Donors and PHLPP1-Expressing CLL Cells....................................................................................................... 133 4.3.6 PHLPP1 mRNA Stability Differs between CLL Cells, Healthy B Cells and B Cell Lines..................................................................................... 141 4.4 Discussion ................................................................................................... 143 4.5 Materials and Methods ................................................................................ 146 Acknowledgements ........................................................................................... 152 References ........................................................................................................ 153 CHAPTER 5 Phosphoproteomics Methodology: Phosphoproteomic Analysis of Chemokine Signaling Networks. O’Hayre et al. (2009) Methods Enzymol 460:331- 46. ................................................................................................................................. 158 Contents ...........................................................................................................
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