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Two distinct nodes of translational inhibition in the Integrated Stress Response
( Hyung Don Ryoo ),( Deepika Vasudevan ) 생화학분자생물학회(구 한국생화학분자생물학회) 2017 BMB Reports Vol.50 No.11
The Integrated Stress Response (ISR) refers to a signaling pathway initiated by stress-activated eIF2α kinases. Once activated, the pathway causes attenuation of global mRNA translation while also paradoxically inducing stress response gene expression. A detailed analysis of this pathway has helped us better understand how stressed cells coordinate gene expression at translational and transcriptional levels. The translational attenuation associated with this pathway has been largely attributed to the phosphorylation of the translational initiation factor eIF2α. However, independent studies are now pointing to a second translational regulation step involving a downstream ISR target, 4E-BP, in the inhibition of eIF4E and specifically cap-dependent translation. The activation of 4E-BP is consistent with previous reports implicating the roles of 4E-BP resistant, Internal Ribosome Entry Site (IRES) dependent translation in ISR active cells. In this review, we provide an overview of the translation inhibition mechanisms engaged by the ISR and how they impact the translation of stress response genes. [BMB Reports 2017; 50(11): 539-545]
Invited Mini Review : Drosophila as a model for unfolded protein response research
( Hyung Don Ryoo ) 생화학분자생물학회(구 한국생화학분자생물학회) 2015 BMB Reports Vol.48 No.8
Endoplasmic Reticulum (ER) is an organelle where most secretory and membrane proteins are synthesized, folded, and undergo further maturation. As numerous conditions can perturb such ER function, eukaryotic cells are equipped with responsive signaling pathways, widely referred to as the Unfolded Protein Response (UPR). Chronic conditions of ER stress that cannot be fully resolved by UPR, or conditions that impair UPR signaling itself, are associated with many metabolic and degenerative diseases. In recent years, Drosophila has been actively employed to study such connections between UPR and disease. Notably, the UPR pathways are largely conserved between Drosophila and humans, and the mediating genes are essential for development in both organisms, indicating their requirement to resolve inherent stress. By now, many Drosophila mutations are known to impose stress in the ER, and a number of these appear similar to those that underlie human diseases. In addition, studies have employed the strategy of overexpressing human mutations in Drosophila tissues to perform genetic modifier screens. The fact that the basic UPR pathways are conserved, together with the availability of many human disease models in this organism, makes Drosophila a powerful tool for studying human disease mechanisms. [BMB Reports 2015; 48(8): 445-453]
Role of <i>Drosophila</i> EDEMs in the degradation of the alpha-1-antitrypsin Z variant
JANG, BO-YUN,RYOO, HYUNG DON,SON, JAEKYOUNG,CHOI, KYUNG-CHUL,SHIN, DONG-MYOUNG,KANG, SANG-WOOK,KANG, MIN-JI UNKNOWN 2015 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE Vol.35 No.4
<P>The synthesis of proteins in the endoplasmic reticulum (ER) that exceeds the protein folding capacity of this organelle is a frequent cause of cellular dysfunction and disease. An example of such a disease is alpha-1-antitrypsin (A1AT) deficiency, caused by destabilizing mutations in this glycoprotein. It is considered that the mutant proteins are recognized in the ER by lectins and are subsequently degraded through the proteasome, leading to a deficiency in this enzyme in the afflicted patients. We previously established a <I>Drosophila</I> model of this disease by overexpressing the null Hong Kong (NHK) allele of this gene and found that the <I>Drosophila</I> lectin, ER degradation-enhancing α-mannosidase-like protein 2 (EDEM2), can accelerate the degradation of A1AT when overexpressed. NHK is a rare allele, and in this study, we investigated in depth the mechanisms through which <I>Drosophila</I> EDEMs affect the degradation of the Z variant, which is the predominant disease allele. Specifically, we report that the Z allele does not activate ER stress signaling as prominently as the NHK allele, but similarly requires both <I>Drosophila</I> EDEM1 and EDEM2 for the degradation of the protein. We demonstrate that EDEMs are required for their ubiquitination, and without EDEMs, glycosylated A1AT mutants accumulate in cells. These results support the role of the EDEM-mediated ubiquitination of the alpha-1-antitrypsin Z (ATZ) allele, and establish a <I>Drosophila</I> model for the study of this protein and disease.</P>
홈네트워킹 환경을 위한 지니 룩업서비스와 디스 커버리 프로토콜의 개선
류대희(Dae-Hee Ryoo),윤형민(Hyung-Min Yoon),한탁돈(Tack-Don Han) 한국정보과학회 2001 한국정보과학회 학술발표논문집 Vol.28 No.2Ⅰ
지니 기술은 자바 프로그래밍 모델을 기초로 한 클라이언트가 동적으로 서비스를 찾아서 프래그 앤 플레이를 가능하게 해주는 기술이다. 홈네트워킹 환경에 이러한 기술을 적용하였을 때, 허가되지 않은 사용자들이 접근할 수 있어 네트워크 보안에 관한 문제가 발생한다. 또한 룩업서비스에 서비스를 등록한 정보 가전 시스템의 관리를 필요로 한다. 그래서 본 논문은 지니 룩업서비스에 사용자가 접근할 때 인증의 과정을 거치도록 하였고, 정보 가전 시스템의 관리를 위한 기능을 추가하였다.
Kim, Hawk,Lee, Won-Sik,Lee, Kyoo-Hyung,Bae, Sung Hwa,Kim, Min Kyoung,Joo, Young-Don,Zang, Dae Young,Jo, Jae-Cheol,Lee, Sang Min,Lee, Je-Hwan,Lee, Jung-Hee,Kim, Dae-Young,Ryoo, Hun-Mo,Hyun, Myung Soo,K Springer International 2015 Annals of hematology Vol.94 No.5
<P>The practical usefulness of Helicobacter pylori eradication for immune thrombocytopenia (ITP) patients is still controversial. However, some ITP patients respond to H. pylori eradication. We conducted a multi-center, open label, prospective phase II study to define the efficacy and toxicities of H. pylori eradication as the first line treatment for persistent or chronic ITP patients with moderate thrombocytopenia. Patients with persistent or chronic ITP showing moderate thrombocytopenia (30??10(9)/L??platelet count??70??10(9)/L) and positive C(13)-urea breath test (UBT) were selected. Medication consisted of lansoprazole 30 mg, amoxicillin 1000 mg, and clarithromycin 500 mg orally twice daily for a week. Complete response (CR) rate at 4 weeks, 3 months, 6 months, 12 months, and maximal response was 19.2, 50.0, 50.0, 26.9, and 65.4%, respectively. Overall response rate (ORR) at 4 weeks, 3 months, 6 months, 12 months, and maximal response was 19.2, 57.7, 65.4, 30.8, and 69.2%, respectively. Median maximal platelet count during the first 3 months was 110??10(9)/L (range, 40-274). Median time to CR was 8 weeks (95% CI?=?5.429-10.571). Median time to ORR was 4 weeks (95% CI?=?1.228-6.772). Only per-protocol population was a response predictor for ORR at 3 months (70.0%, p?=?0.054) and maximal ORR (80.0%, p?=?0.051), but not for CR at 3 months (60.0%, p?=?0.160). Therefore, eradication of H. pylori is an effective and durable first line treatment for persistent or chronic ITP with moderate thrombocytopenia with high ORR and rapid onset in this study.</P>
Kang, Sang-Won,Hong, Sung-Yu,Ryoo, Hyung-Don,Rhyu, Gyung-Ihm,Kim Yu-Sam Korean Chemical Society 1994 Bulletin of the Korean Chemical Society Vol.15 No.5
The catalytic mechanism of malonyl-CoA synthetase from Rhizobium trifolii was investigated by the steady state kinetics and intermediate identification. Initial velocity studies and the product inhibition studies with AMP and PPi strongly suggested ordered Bi Uni Uni Bi Ping-Pong Ter Ter system as the most probable steady state kinetic mechanism of malonyl-CoA synthetase. Michaelis constants were $0.17{\pm}0.04 {\mu}M,\;0.24{\pm}0.18 {\mu}M\;and\;0.045{\pm}0.26 {\mu}$M for ATP, malonate and CoA, respectively. The TLC analysis of the $^{32}P-labelled$ products in reaction mixture containing $[{\gamma}-^{32}P]$ ATP in the absence of CoA showed that PPi was produced after the sequential addition of ATP and malonate. Formation of malonyl-AMP, suggested as an intermediate in the kinetically deduced mechanism, was confirmed by the analysis of $^{31}P-NMR$ spectra of AMP product isolated from the $^{18}O$ transfer experiment using $[^{18}O]$malonate. Two resonances were observed, corresponding to AMP labelled with zero and one atom of $^{18}O$, indicating that one atom of $^{18}O$ transferred from $[^{18}O]$malonate to AMP through the formation of malonyl-AMP. Formation of malonyl-AMP was also confirmed through the TLC analysis of reaction mixture containing $[{\alpha}-^{32}P]$ATP. These results strongly support the ordered Bi Uni Uni Bi Ping-Pong Ter Ter mechanism deduced from the initial velocity and product inhibition studies.
Kim, Hawk,Lee, Je-Hwan,Joo, Young-Don,Bae, Sung Hwa,Hyun, Myung Soo,Lee, Jung-Hee,Kim, Dae-Young,Lee, Won-Sik,Ryoo, Hun Mo,Kim, Min Kyoung,Park, Jae-Hoo,Lee, Kyoo-Hyung Springer International 2012 Annals of hematology Vol.91 No.9
<P>Recently, a less toxic regimen comprising reduced cyclophosphamide (Cy), fludarabine, and anti-thymocyte globulin (ATG) (Cy-Flu-ATG) was used to condition high-risk patients scheduled for allogeneic hematopoietic cell transplantation (alloHSCT) instead of standard Cy-ATG in patients with severe aplastic anemia (AA). We performed a randomized phase III study to compare the regimen-related toxicities (RRTs) of two different conditioning regimens: Cy-ATG vs. Cy-Flu-ATG. Patients in the Cy-ATG arm received Cy at 200 mg/kg. Those in the Cy-Flu-ATG arm received fludarabine (Flu) at 150 mg/m(2) and Cy at 100 mg/kg. A total of 83 patients (40 in the Cy-ATG and 43 in the Cy-Flu-ATG) were enrolled. Seventy-nine patients had AA and four had MDS. All predefined RRTs were significantly lower in patients of the Cy-Flu-ATG arm (23.3 vs. 55.0 %; p = 0.003). Infection with identified causative organism and sinusoidal obstruction syndrome, hematuria, febrile episodes, and death from any cause tended to be more frequent in Cy-ATG arm but did not differ significantly between arms. There was no difference in neutrophil engraftment failure (2.5 vs. 2.33 %; p = 0.959), acute graft-versus-host disease (GvHD) (15.0 vs. 23.3 %; p = 0.388), and chronic GvHD (16.7 vs. 16.2 %; p = 0.961) between Cy-ATG and Cy-Flu-ATG arms. The 4-year survival rate did not differ between the Cy-ATG and Cy-Flu-ATG arms. Preconditioning with Cy-Flu-ATG was superior to that afforded by Cy-ATG in terms of reducing RRT levels without increasing engraftment failure.</P>