Ubiqutin-modifying enzymes, A20 and Pellino-1. as therapeutic targets …

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  • Writer 최고관리자
  • 2018-09-10


[2018 Fall Life Sciences & IBB  Seminar]

▶Subject: Ubiqutin-modifying enzymes, A20 and Pellino-1. as therapeutic targets in cancer metastasis and inflammation

 ▶Speaker: Prof. Seok Hee Park (Sungkyunkwan University)

 ▶Date: 4:30PM/Sept. 14(Fri.)/ 2018

▶Place: Auditorium(1F), Postech Biotech Center

The ubiquitin-editing enzyme A20 has been known to be a key player in inflammation and contains the deubiquitinase and E3 ligase activities. Although extensive studies suggest a role of A20 enzyme in cancer, its molecular mechanism in cancer metastasis remains unknown. Here we demonstrate that A20 monoubiquitinates Snail1 at three lysine residues and thereby promotes metastasis of aggressive basal-like breast cancers. A20 is significantly upregulated in human basal-like breast cancers and its expression level is inversely correlated with metastasis-free patient survival. A20 facilitates TGF-1-induced epithelial-mesenchymal transition (EMT) of breast cancer cells through multi-monoubiquitination of Snail1. Knockdown of A20 or overexpression of Snail1 with mutations of the monoubiqutinated lysine residues into arginine abolishes lung metastasis in mouse xenograft and orthotopic breast cancer models, indicating that A20 and monoubiqutinated Snail1 are required for metastasis. These findings uncover an essential role of A20-Snail1 axis in TGF-1-induced EMT and metastasis of basal-like breast cancers.
In this meeting, we also discuss the development of Smaducin-6 targeting the E3 ligase Pellino-1 in inflammatory diseases. Smaducin-6 has been developed as a novel membrane-tethered  palmitic acid-conjugated Smad6-derived peptide. Smaducin-6 interacts with Pellino-1, located in the inner membrane, thereby disrupted the formation of IRAK1-, RIP1-, IKKε-mediated TLR4 signaling complexes. Systemic administration of Smaducin-6 shows a significant therapeutic effect on mouse TLR4-mediated inflammatory disease models, cecal-ligation-puncture (CLP)-induced sepsis and lipopolysaccharide-induced endotoxemia, by inhibiting pro-inflammatory cytokine production and apoptosis, while enhancing neutrophil migration and bacterial clearance. Our findings provide clues to develop new peptide-based drugs to target Pellino-1 protein in TLR4 signaling pathway for the treatment of sepsis.

▶Inquiry:  Cheol-Sang Hwang (279-2352)

* This seminar will be given in  Korean.
  Please refrain from taking photos during seminars. *