연구논문

세부과제번호 2013M3A9D5072550 단계 1단계 2차년도
세부과제명 마우스운동 및 대사표현형 분석 기반 구축 및 서비스 제공 공동 유/무 -
SCI여부 Y 게재년월 2015-10
논문제목 Glutamine contributes to maintenance of mouse embryonic stem cell self-renewal through PKC-dependent downregulation of HDAC1 and DNMT1/3a.
총저자명 Jung Min RyuSang Hun LeeJe Kyung SeongHo Jae Han
학술지명 Cell Cycle 게재권(호) 14(20)
저널구분 SCI 페이지수 3292-3305
참여연구원 - 연구책임자 성제경
과제기여도 50 PMID 26375799
사사기관수 2 IF (년도) 4.565(
제1저자 Jung Min Ryu 교신저자 -
공동저자 Sang Hun Lee
초록
Although glutamine (Gln) is not an essential amino acid, it is considered a critical substrate in many key metabolic processes that control a variety of physiological functions and are involved in regulating early embryonic development. Thus, we investigated the effect of Gln on regulation of mouse embryonic stem cell (mESC) self-renewal and related signaling pathways. Gln deprivation decreased Oct4 expression as well as expression of cell cycle regulatory proteins. However, Gln treatment retained the expression of cell cycle regulatory proteins and the Oct4 in mESCs, which were blocked by compound 968 (a glutaminase inhibitor). In addition, Gln stimulated PI3K/Akt pathway, which subsequently elicited PKCϵ translocation to membrane without an influx of intracellular Ca(2+). Inhibition of Akt and PKC blocked Gln-induced Oct4 expression and proliferation. Gln also stimulated mTOR phosphorylation in a time-dependent manner, which abolished by PKC inhibition. Furthermore, Gln increased the cellular population of both Oct4 and bromodeoxyuridine positive cells, suggesting that Gln regulates self-renewal ability of mESCs. Gln induced a decrease in HDAC1, but not in HDAC2, which were blocked by PKC inhibitors. Gln treatment resulted in an increase in global histone acetylation and methylation. In addition, Gln significantly reduced methylation of the Oct4 promoter region through decrease in DNMT1 and DNMT3a expression, which were blocked by PKC and HDAC inhibitors. In conclusion, Gln stimulates mESC proliferation and maintains mESC undifferentiation status through transcription regulation via the Akt, PKCϵ, and mTOR signaling pathways.
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