Studies on the Epigenetic and Transcriptional Regulation of LSD1 in Inflammatory Response

다국어 초록 (Multilingual Abstract)

The inflammatory response is an essential host defense mechanism against invading pathogens. NF-κB signaling plays a key role in regulating the inflammatory response, and misregulation of NF-κB signaling is involved in cancer and autoimmune disease. Although protein kinase C (PKC) signaling is shown to be crucial for the activation of the inflammatory response, the molecular mechanism of activation of the inflammatory response by PKC remains unclear. Here, I find that PKCα is translocated into the nucleus in response to inflammatory signal and directly phosphorylates lysine specific demethylase 1 (LSD1) in the nucleus. Lipopolysaccharide (LPS)-induced LSD1 phosphorylation by PKCα is required for its interaction with p65, and phosphorylated LSD1 facilitates demethylation of p65 leading to enhanced p65 protein stability. Genome-wide analysis reveals that LPS-induced LSD1 phosphorylation leads to activation of NF-κB target genes involved in sepsis. Importantly, Lsd1SA/SA mice with ablation of LSD1 phosphorylation show attenuated LPS-induced lung inflammatory injury and sepsis-induced mortality with greater survival rates than wild-type (WT) mice. Together, our data indicate that targeting PKCα signaling with its downstream LSD1 could be potentially powerful therapeutic strategy for inflammatory diseases such as sepsis.

목차 (Table of Contents)

• CHAPTER I. Introduction 1
• I-1. Lysine-specific demethylase 1 (LSD1) 2
• 1.1. Physiological functions of LSD1 2
• 1.2. Phosphorylation of LSD1 3
• I-2. Protein kinase Cα (PKCα) 5
• 2.1. Structure of PKC family 5
• 2.2. Regulations of PKCα 6
• I-3. Nuclear factor-kappa B (NF-κB) 8
• 3.1. Structure of NF-κB family 8
• 3.2. NF-κB signaling pathway 10
• 3.3. Physiological functions of NF-κB 11
• I-4. Inflammation 13
• 4.1. The function of inflammation 13
• 4.2. Epigenetic and transcriptional regulation of inflammation 13
• 4.3. Septic Shock and Sepsis 14
• CHAPTER II. LSD1 phosphorylation by PKCα is crucial for LPS-induced inflammatory responses 17
• II-1. Summary 18
• II-2. Introduction 19
• II-3. Results 21
• II-4. Discussion 42
• II-5. Materials and Methods 45
• CHAPTER III. Demethylation of p65 by LSD1 enhances protein stability of p65 55
• III-1. Summary 56
• III-2. Introduction 57
• III-3. Results 59
• III-4. Discussion 80
• III-5. Materials and Methods 83
• CHAPTER IV. Conclusion 96
• REFERENCES 100
• 국문초록 / ABSTRACT IN KOREAN 119