• 한국발생생물학회지:발생과생식
• /
• 제11권2호
• /
• pp.59-66
• /
• 2007

배아줄기세포를 이용한 치료법 개발을 위해서는 배아줄기세포의 자가재생산 및 분화과정을 조절하는 분자적 기전을 이해하는 것이 매우 중요하다. 지질합성경로(Mevalonate pathway)에 작용하는 HMG-CoA 환원효소(Hydroxymethylglutaryl-coenzyme A reductase)의 억제제인 스타틴은 콜레스테롤 저하제로 잘 알려져 있으며, 콜레스테롤 이외에 단백질 isoprenylation의 기질로 작용하는 아이소프레노이드(Isoprenoids)(Farnesyl pyrophosphate(FPP), Geranylgeranyl pyrophosphate(GGPP))의 생성을 억제하는 효능을 가지고 있다. 스타틴에 의해 매개되는 표적단백질의 isoprenylation 억제는 다양한 세포내 신호전달과정에 영향을 미치게 되며, 결과적으로 세포기능을 조절하는데 핵심적인 역할을 하게 된다. 스타틴이 첨가된 배양배지에서 배양된 배아줄기세포는 자가재생산능이 억제되고 분화가 촉진되는데, 특히 지방/골세포 직계열로의 분화가 촉진된다. 배아줄기세포에서의 스타틴의 효과 및 작용기전에 대한 이해가 아직은 미비한 수준이나, 최근 우리 연구팀에서는 스타틴이 콜레스테롤 작용과는 무관하게 RhoA G-단백질의 세포내 분포 및 활성을 억제함으로써 배아 줄기세포의 자가재생산능을 억제하고 있음을 규명하였다. 스타틴 다면효과와 그 작용에 대한 이해는 배아줄기세포의 미분화 및 분화상태를 조절하는데 관여하는 분자적 조절기전을 이해하는데 중요한 모델이 될 수 있을 것으로 추정된다.

• Molecules and Cells
• /
• 제28권1호
• /
• pp.49-55
• /
• 2009

Hepatitis delta virus (HDV) infection causes fulminant hepatitis and liver cirrhosis. To elucidate the molecular mechanism of HDV pathogenesis, we examined the effects of HDV viral proteins, the small hepatitis delta antigen (SHDAg) and the large hepatitis delta antigen (LHDAg), on $NF-{\kappa}B$ signaling pathway. In this study, we demonstrated that $TNF-{\alpha}-induced$ $NF-{\kappa}B$ transcriptional activation was increased by LHDAg but not by SHDAg in both HEK293 and Huh7 cells. Furthermore, LHDAg promoted TRAF2-induced $NF-{\kappa}B$ activation. Using coimmunoprecipitation assays, we demonstrated that both SHDAg and LHDAg interacted with TRAF2 protein. We showed that isoprenylation of LHDAg was not required for the increase of $NF-{\kappa}B$ activity. We further showed that only LHDAg but not SHDAg increased the $TNF-{\alpha}-mediated$ nuclear translocation of p65. This was accomplished by activation of $I{\kappa}B_{\alpha}$ degradation by LHDAg. Finally, we demonstrated that LHDAg augmented the COX-2 expression level in Huh7 cells. These data suggest that LHDAg modulates $NF-{\kappa}B$ signaling pathway and may contribute to HDV pathogenesis.

• Archives of Pharmacal Research
• /
• 제21권4호
• /
• pp.378-384
• /
• 1998

The processing pathway of G-proteins and Ras family proteins includes the isoprenylation of the cysteine residue, followed by proteolysis of three terminal residues and .alpha.-carboxyl methyl esterification of the cysteine residue. Farnesylcysteine methyltransferase (FCMT) activity is responsible for the methylation reaction which play a role in the membrane attachment of a variety of cellular proteins. Four kinds of Ras protein (c-Ha-ras, c-N-Ras, c-Ki-Ras, pan-Ras) expression were detected in adenocarcinoma of human tissue by immunohistochemical method, and hematoxylin and eosin staining. The level of Ras protein in human stomach tumor tissues was much higher than in normal and peritumoral regions of the same biopsy samples. The FCMT activities of each cellular fractions were high in mitochondrial fraction followed by microsomal fraction, whole homogenate and cytosolic fraction. The inhibitory effect on FCMT activity on stomach tumor tissue was determined after treatment with 0.25 $\mu\textrm{M}$ of S-adenosyl-$_L$-homocysteine. S-adenosyl-$_L$-homocysteine inhibited FCMT activity from 11.2% to 30.5%. These results suggested that FCMT might be involved in Ras proteins activity.