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Studies on the Epigenetic and Transcriptional Regulation of LSD1 in Inflammatory Response : 염증 반응에서 LSD1의 후성 유전 및 전사 조절 기작에 대한 연구
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- Authors
- Advisor
- 백성희
- Major
- 자연과학대학 생명과학부
- Issue Date
- 2018-02
- Publisher
- 서울대학교 대학원
- Keywords
- Lysine-specific demethylase 1 (LSD1) ; Protein kinase Cα (PKCα) ; Phosphorylation ; Epigenetic regulation ; Nuclear factor-kappa B (NF-κB) ; p65 ; CCAAT-enhancer-binding proteins (C/EBPs) ; Transcription ; Lipopolysaccharide (LPS) ; Inflammation ; Sepsis.
- Description
- 학위논문 (박사)-- 서울대학교 대학원 : 자연과학대학 생명과학부, 2018. 2. 백성희.
- 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.
- Language
- English
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