PDGF UPREGULATES MCL-1 THROUGH ACTIVATION OF β-CATENIN AND HIF-1α-DEPENDENT SIGNALING IN CANCER Pubblico

Abstract

PDGF UPREGULATES MCL-1 THROUGH ACTIVATION OF β-CATENIN AND HIF-1α-DEPENDENT SIGNALING IN CANCER
By Shareen Iqbal

Background: Aberrant platelet derived growth factor (PDGF) signaling has been associated with cancer progression. However, its role in the regulation of cancer cell growth and survival has not been well characterized.

Methodology/Principal Findings: Prostate cancer (PCa) was employed as a model system. Using experimental models that closely mimic clinical pathophysiology of PCa progression, this study demonstrated that PDGF is a survival factor in PCa cells through upregulation of myeloid cell leukemia-1 (Mcl-1). PDGF treatment induced rapid nuclear translocation of β-catenin, presumably mediated by c-Abl and p68 signaling. Intriguingly, PDGF promoted formation of the nuclear transcriptional complex of β-catenin and hypoxia-inducible factor (HIF)-1α, and the binding of HIF-1α to Mcl-1 promoter. Deletion of a putative hypoxia response element (HRE) within the Mcl-1 promoter attenuated PDGF effects on Mcl-1 expression. Blockade of PDGF receptor (PDGFR) signaling with a pharmacological inhibitor AG-17 abrogated PDGF induction of Mcl-1, and induced apoptosis in metastatic PCa cells.

Conclusions/Significance: This study elucidated a crucial survival mechanism in PCa cells, indicating that interruption of the PDGF-Mcl-1 survival signal may provide a novel strategy for treating PCa metastasis. These results can be further applied to other model systems of tumorigenesis.

PDGF UPREGULATES MCL-1 THROUGH ACTIVATION OF β-CATENIN AND HIF-1α-DEPENDENT SIGNALING IN CANCER
By
Shareen Iqbal
B.A., Indiana University, 2003
Advisor: Leland Chung, PhD
A dissertation submitted to the Faculty of the
James T. Laney School of Graduate Studies of Emory University
in partial fulfillment of the requirements for the degree of
Doctor of Philosophy
in Graduate Division of Biological and Biomedical Science, Neuroscience
2011

Table of Contents

Table of Contents
List of Tables...viii
List of Figures...ix

CHAPTER 1--Introduction...1

1.1 Structural Properties of PDGFs and PDGFRs...1
1.2 PDGF Receptors...2
1.3 PDGF Signaling Cascade...3
1.4 PDGF Functions...4
1.5 PDGF and Neuroscience...5
1.6 PDGF Activation in Cancer...6

1.6.1 Angiogenesis...9
1.6.2 Proliferation...11
1.6.3 Metastasis...11

1.7 Mcl-1...12
1.8 Mcl-1 and Neuroscience...15
1.9 Mcl-1 and Cancer...16
1.10 Mcl-1 as an Attractive Target for Cancer Therapy...16

CHAPTER 2--Materials and Methods...18

2.1 Cell Culture...18
2.2 Plasmids and Small Interfering RNAs (siRNAs)...18
2.3 Western Blot Analysis...19
2.4 Immunoprecipitation...20
2.5 Immunofluorescence and Confocal Imaging...20
2.6 Reverse Transcription-PCR (RT-PCR)...21
2.7 Chromatin Immunoprecipitation Assay (ChIP)...22
2.8 Statistical Analysis...22

CHAPTER 3--Results...23
CHAPTER 4--Discussion...37

References...45
Autobiographical Statement...59

About this Dissertation

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• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, General
Parola chiave	Cancer
Committee Chair / Thesis Advisor	Chung, Leland, Cedars Sinai
Committee Members	Hall, Randy A, Emory University Joshi, Harish C, Emory University Ye, Keqiang, Emory University Chan, Anthony, Emory University

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