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Screening of Phosphoserine aminotransferase 1 Inhibitor Based on a Structural Feature : Phosphoserine aminotransferase1의 구조적 특성을 기반으로 한 저해제 발굴
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- Authors
- Advisor
- 윤홍덕
- Major
- 융합과학기술대학원 분자의학 및 바이오제약학과
- Issue Date
- 2017-02
- Publisher
- 서울대학교 대학원
- Keywords
- phosphoserine aminotransferase 1 ; cancer stem cell
- Description
- 학위논문 (석사)-- 서울대학교 대학원 : 융합과학기술대학원 분자의학 및 바이오제약 전공, 2017. 2. 윤홍덕.
- Abstract
- Phosphoserine aminotransferase 1 (Psat1) is a transaminase involved in de novo serine biosynthesis pathway generating α-ketoglutarate (α-KG) (Baek et al., 2003). α-KG is a cofactor of α-KG-dependent dioxygenases including ten-eleven translocation (Tet) family of DNA hydroxylases and Jumanji C-domain-containing histone demethylases (JHDMs) (Kaelin and McKnight, 2013). Specifically Psat1 directs a-KG level thereby regulating epigenetic landscape for maintaining pluripotency in mouse embryonic stem cells (mESCs) (Hwang et al., 2016).
Cancer stem cells (CSCs) are subpopulation of tumor which, like stem cells, can self-renew and differentiate into the cells consisting of the tumor. Eradication of CSCs is critical for fundamental cancer treatment because CSCs can cause cancer recurrence (Nassar and Blanpain, 2016
Reya et al., 2001).
In this study, it was showed that PSAT1 has positive correlation with OCT4, a core pluripotency transcription factor, in breast cancer and specifically is highly expressed in basal-like subtype which has large enrichment of breast CSCs relative to other subtypes. Based on these, it was expected that inhibition of Psat1 activity can induce differentiation of CSCs, after all, removal of CSCs. Therefore, we tried to identify Psat1 inhibitor which reduces Psat1 activity by blocking active structural formation. First, it was confirmed that Psat1 forms a homo-dimer structure. Screening for identifying Psat1 dimerization inhibitor was performed using 3920 chemicals in mammalian two hybrid system, a powerful tool which can detect protein-protein interaction. As a result, 1 candidate chemical was found. Although screening to more chemicals should be performed, it is anticipated that Psat1 inhibitor can open new era for cancer therapy.
- Language
- English
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