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The Pennsylvania State University the Graduate School the Huck Institutes for Life Sciences MODULATION of NUCLEAR FACTOR KAPPA B

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The Pennsylvania State University the Graduate School the Huck Institutes for Life Sciences MODULATION of NUCLEAR FACTOR KAPPA B The Pennsylvania State University The Graduate School The Huck Institutes for Life Sciences MODULATION OF NUCLEAR FACTOR KAPPA B (NFκB) TRANSACTIVATION BY TRANSFORMING GROWTH FACTOR β-1 (TGFβ-1) IN KERATINOCYTES: IMPLICATIONS FOR RESPONSIVENESS TO ULTRAVIOLET RADIATION (UVB) A Dissertation in Integrative Biosciences by Kelly A. Hogan ©2011 Kelly A. Hogan Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy December 2011 The dissertation of Kelly A. Hogan was reviewed and approved* by the following: Adam B. Glick Associate Professor of Veterinary and Biomedical Sciences Dissertation Advisor Chair of Committee John Vanden Heuvel Professor of Veterinary and Biomedical Sciences Andrea Mastro Professor of Microbiology and Cell Biology K. Sandeep Prabhu Associate Professor of Immunology and Molecular Toxicology Avery August Distinguished Adjunct Professor of Immunology Peter Hudson Willaman Professor of Biology Director, Huck Institutes of the Life Sciences *Signatures are on file in the Graduate School ii Abstract Molecular crosstalk leading to the integration of signal transduction pathways—and the formation of a signaling network—is particularly important for maintaining cellular homeostasis. Stimuli received at the cell surface and transduced to the nucleus can expect to be modified by any number of inputs in a highly context-dependent and cell-specific manner. Nuclear factor kappa B (NFκB) and transforming growth factor β-1 (TGFβ-1) are not only critical factors mediating inflammation, but they also play a substantial role in cancer progression. Therefore, understanding the intersection of these factors may shed light on inflammatory diseases and progression of cancer in skin. However, little is known about how TGFβ-1 and NFκB interact in keratinocytes, which rely heavily on both factors to maintain homeostasis. These studies provide data in keratinocytes that suggest TGFβ-1 modulated NFκB-dependent expression of proinflammatory cytokines, namely TNFα. Although results in these studies fail to show TGFβ- 1-mediated activation of upstream molecules of the canonical NFκB pathway or translocation of NFκB, preliminary evidence reveals that TGFβ-1 activating kinase (TAK-1) may provide a molecular link between TGFβ-1 receptor activation and NFκB transactivation. In spite of the fact that upstream signaling events are only speculative and part of ongoing inquiry, results presented in this chapter support the hypothesis that TGFβ-1-mediated NFκB transactivation of gene expression is Smad3-dependent. Furthermore, TGFβ-1 potentiates NFκB binding to consensus DNA sites, which putatively involves both the p50 and p65 subunit. The biological relevance of TGFβ-1 and NFκB crosstalk leading to expression of proinflammatory cytokines is also explored. Preliminary evidence suggests that this pathway may have a role in TGFβ-1- mediated apoptosis, differentiation, and ras-mediated induction of NFκB-dependent genes in keratinocytes. These studies are the first to show an intersection between TGFβ-1 and NFκB pathways, which may represent a mechanism by which TGFβ-1 ‘tunes’ or modulates NFκB- dependent gene expression. The biological relevance of TGFβ-1-mediated TNFα was then explored in the context of ultraviolet radiation responsiveness, which elicits an inflammatory response involving the proinflammatory cytokine TNFα. Ultraviolet radiation, particularly the UVB wavelengths ranging from 280-320 nm, is a whole carcinogen capable of initiating and promoting squamous cell carcinoma (SCC), among other types of skin cancer, in both humans and laboratory rodents after repeated UVB exposure over time. Responsiveness to UVB, specifically, has not been particularly well-characterized in keratinocytes. Presently, the literature reflects more rigorous characterization of the UVC wavelengths in cell types that are typically not sun-exposed. Furthermore, published studies using the mouse as a model to inquire into TGFβ-1-mediated UVB responsiveness are non-existent. The present studies, performed in mouse and in primary keratinocytes isolated from mouse, demonstrate the intersection of TGFβ-1 and NFκB in the context of UVB responsiveness. Specifically, the hypothesis to be tested predicts that response to UVB will be partially dependent on TGFβ-1 signaling. UVB treated mice and keratinocytes in culture demonstrated Smad3- and NFκB-dependent expression of the proinflammatory iii cytokine TNFα between 2-6 h post treatment and required an intact TGFβ-1 signaling pathway. Furthermore, an acute decrement in Smad7 expression was observed initially, but restored to control levels by 6 h. Smad7 repression also appears to be partially Smad3 dependent. The results of these studies also demonstrated for the first time TGFβ-1-mediated NFκB binding of p50 and p65 subunits to DNA following UVB exposure. Although degradation of IκB or translocation of the p50 subunit was not observed, the data presented herein suggested a scenario whereby the NFκB-dependent proinflammatory cytokine was expressed in a p50- and Smad3- dependent manner. Taken together, it is likely that TGFβ-1 is among the pathways involving NFκB transactivation that modulate or tune response to UVB. iv Table of Contents List of Figures ix-xiii List of Tables xiv Abbreviations xv Acknowledgements xvi-xviii Chapter 1: Introduction 1-64 I TGFβ-1 Signaling 1-8 A. Bioactivation of Latent TGFβ-1 1-2 B. TGFβ-1 Receptors 2-4 C. Smads 4-7 1) Smads in Skin 7-8 II TGFβ-1 Biology in Skin 8-18 A. Structure and Function of Skin 8-11 1) TGFβ-1 in Growth Inhibition and Senescence 11-12 2) TGFβ-1 in Apoptosis 12 3) TGFβ-1 in Terminal Differentiation 12-13 B. Role of TGFβ-1 in Immune Modulation 13-14 C. Role of TGFβ-1and Smads in Carcinogenesis 14-15 1) TGFβ-1 and Ras in Cancer Progression 15-16 2) TGFβ-1 in Tumor Immunology and Inflammation 17-18 III NFκB Signaling in Skin 18-23 A. Canonical NFκB pathway 18-22 B. NFκB Transactivation 22-23 IV Role of NFκB in Skin Homeostasis 23-33 A. Role of NFκB in Growth Inhibition and Senescence 24-25 B. Role in Terminal Differentiation 25-26 C. Role of NFκB in Apoptosis 26-27 D. Role of NFκB in Immune Modulation 27-28 1) TNFα in skin 28-31 E. Role of NFκB in Carcinogenesis 31-33 v V Ultraviolet Radiation (UVR) Responsiveness in Skin 33-39 A. Acute Responses to UVR in Skin 35-36 B. Chronic UVR Exposure and Skin Carcinogenesis 36-37 C. Role of NFκB in UVB Responsiveness 37-38 D. Role of TGFβ-1 in UVB Responsiveness 38-39 VII Crosstalk between TGFβ-1 and NFκB 39-40 VIII Hypothesis and Aims 40-41 IX Literature Cited 41-64 Chapter 2: TGFβ-1 Crosstalk: Intersections between NFκB or Ras and TGFβ-1 Signaling in Keratinocytes 65-145 I Abstract 65 II Introduction 65-66 III Materials and Methods 66-74 A. Materials 66-67 B. Animal studies 67 C. Isolation of keratinocytes 67-68 D. Cell culture 68 E. Cell viability assay 68 F. Caspase 3/7 assay 68-69 G. Preparation of whole cell lysates 69 H. Western analysis 69 I. Preparation of nuclear extract 69-70 J. Electrophoretic mobility shift assay 70-71 K. Supershift assay 71 L. RNA isolation 71 M. cDNA synthesis 71-72 N. qPCR 72 O. v-Ha-Ras transduction 72 P. Luciferase assay 72-73 Q. siRNA transfection 73 R. Adenoviral infection 73 S. Statistical analysis 73-74 IV Results 74-124 vi A. TGFβ-1 mediated TNFα expression is NFκB and Smad3 dependent 74-78 B. TGFβ-1 fails to activate upstream NFκB signaling factors, but regulates 78-83 NFκB binding to DNA and transactivation C. TGFβ-1-induced transactivation of NFκB requires Smad-3 and an intact 84-88 NFκB signaling pathway D. Exploration of mechanisms linking TGFβ-1 signaling to NFκB activation 88-100 E. Biological relevance of the TGFβ-1/NFκB intersection 100-116 V Discussion 116-124 A. A novel target of TGFβ-1-mediated NFκB-dependent gene expression 116-118 B. Failure of TGFβ-1 to activate upstream molecules in the canonical NFκB 118-119 signaling pathway C. Smad3 interaction with NFκB during NFκB transactivation 119-122 D. Biological relevance of TGFβ-1-mediated NFκB 122-124 VI Summary 125 VII Future Directions 125-132 A. Elucidation of NFκB/Smad3 interactions 125-127 B. Kinases as mediators of non-canonical NFκB signaling 127-132 VI Literature Cited 132-145 Chapter 3: Role for TGFβ-1 in NFκB-mediated Response to Ultraviolet Radiation (UVB) in Keratinocytes 146-185 I Abstract 148 II Introduction 148-150 III Materials and Methods 150-156 A. Materials 150 B. Animal studies 150 C. Isolation of keratinocytes and fibroblasts 150-151 D. Cell culture 151 E. In vitro UVB treatment 151-152 F. Preparation of whole cell lysates 152 G. Western analysis 152-153 H. Preparation of nuclear extract 153 I. Electrophoretic mobility shift assay 153-154 J. Supershift assay 154 K. Myeloperoxidase immunohistochemistry 154-155 vii L. RNA isolation 155 M. cDNA synthesis 155 N. qPCR 155-156 O. Luciferase assay 156 P. Statistical analysis 156 IV Results 156-175 A. Ultraviolet radiation (UVB)-induced TNFα is Smad3- and NFκB- 156-164 dependent B. UVB activates the TGFβ-1 pathway, but not the canonical NFκB 164-168 pathway involving TAK-1 C. TGFβ-1 mediates UVB-induced NFκB binding to DNA 168-173 V Discussion 173-178 A. Regulation of UVB-induced proinflammatory cytokines by TGFβ-1 173-175 B. UVB-mediated activation of upstream effectors of the TGFβ-1 signaling 175-176 Pathway C. TGFβ-1-mediated NFκB transcriptional activation 176-178 VI Literature Cited 178-185 Chapter 4: Discussion 186-197 I Global Discussion and Implications 186-197 A. Crosstalk in inflammation: TGFβ-1 and NFκB 186-189 B. NFκB as an amplifier rather than inducer of the ultraviolet radiation (UVR) response in the epidermis 189-192 C.
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