• 생명과학회지
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• 제33권6호
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• pp.523-529
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• 2023

유비퀴틴-프로테아좀 시스템은 E1-E2-E3 효소의 작용으로 단백질 안정성을 조절하며 이를 통해 진핵 세포 내 광범위한 과정을 조절한다. 특히 DNA 수리, 세포 주기, 전이, 혈관형성 및 사멸과 같은 종양의 생장 과정에서 주요한 역할을 하는데 이 과정에서 유비퀴틴 접합 효소인 UBE2는 활성화된 유비퀴틴을 타깃 단백질에 이동시켜주는 중간 매개체 역할을 한다. UBE2는 인간에게서 40개가 존재하며 이는 촉매 도메인의 확장 유무에 따라 4개의 그룹으로 분류된다. 최근 UBE2의 타깃 단백질의 특정 위치를 인식하는 기질 특이성에 대한 연구가 증가하는 추세이다. 특히 암에서 발현이 높은 UBE2는 암 환자의 나쁜 예후와 상관관계가 있어 종양 형성에서 UBE2의 중요성이 강조되고 있다. 본 총설에서는 암에서 UBE2의 역할에 대한 최신 연구 결과 및 동향에 대해 기술하였다. 또한 UBE2에 관한 기초 지식 및 분자적 메커니즘을 제공함으로써 궁극적으로는 UBE2가 종양 치료의 새로운 타깃이 될 수 있음을 시사한다.

• Nutrition Research and Practice
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• 제17권6호
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• pp.1128-1142
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• 2023

BACKGROUND/OBJECTIVES: Inonotus obliquus has been used as antidiabetic herb around the world, especially in the Russian and Scandinavian countries. Diabetes is widely believed to be a key factor in Alzheimer's disease (AD), which is widely considered to be type III diabetes. To investigate whether I. obliquus can also ameliorate AD, it would be interesting to identify new clues for AD treatment. We tested the anti-AD effects of raw Inonotus obliquus polysaccharide (IOP) in a mouse model of AD (3×Tg-AD transgenic mice). MATERIALS/METHODS: SPF-grade 3×Tg-AD mice were randomly divided into three groups (Control, Metformin, and raw IOP groups, n = 5 per group). β-Amyloid deposition in the brain was analyzed using immunohistochemistry for AD characterization. Gene and protein expression of pertinent factors of the ubiquitin-proteasome system (UPS) was determined using real-time quantitative polymerase chain reaction and Western blotting. RESULTS: Raw IOP significantly reduced the accumulation of amyloid aggregates and facilitated UPS activity, resulting in a significant reduction in AD-related symptoms in an AD mouse model. The presence of raw IOP significantly enhanced the expression of ubiquitin, E1, and Parkin (E3) at both the mRNA and protein levels in the mouse hippocampus. The mRNA level of ubiquitin carboxyl-terminal hydrolase isozyme L1, a key factor involved in UPS activation, also increased by approximately 50%. CONCLUSIONS: Raw IOP could contribute to AD amelioration via the UPS pathway, which could be considered as a new potential strategy for AD treatment, although we could not exclude other mechanisms involved in counteracting AD processing.

• Journal of Chest Surgery
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• 제50권3호
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• pp.144-152
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• 2017

Background: The ubiquitin-proteasome system (UPS) is an important pathway of proteolysis in pathologic hypertrophic cardiomyocytes. We hypothesize that MG132, a proteasome inhibitor, might prevent hypertrophic cardiomyopathy (CMP) by blocking the UPS. Nuclear factor kappa-light-chain-enhancer of activated B cells ($NF-{\kappa}B$) and androgen receptor (AR) have been reported to be mediators of CMP and heart failure. This study drew upon pathophysiologic studies and the analysis of $NF-{\kappa}B$ and AR to assess the cardioprotective effects of MG132 in a left ventricular hypertrophy (LVH) rat model. Methods: We constructed a transverse aortic constriction (TAC)-induced LVH rat model with 3 groups: sham (TAC-sham, n=10), control (TAC-cont, n=10), and MG132 administration (TAC-MG132, n=10). MG-132 (0.1 mg/kg) was injected for 4 weeks in the TAC-MG132 group. Pathophysiologic evaluations were performed and the expression of AR and $NF-{\kappa}B$ was measured in the left ventricle. Results: Fibrosis was prevalent in the pathologic examination of the TAC-cont model, and it was reduced in the TAC-MG132 group, although not significantly. Less expression of AR, but not $NF-{\kappa}B$, was found in the TAC-MG132 group than in the TAC-cont group (p<0.05). Conclusion: MG-132 was found to suppress AR in the TAC-CMP model by blocking the UPS, which reduced fibrosis. However, $NF-{\kappa}B$ expression levels were not related to UPS function.

• BMB Reports
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• 제52권2호
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• pp.119-126
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• 2019

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) initiates the extrinsic apoptotic pathway through formation of the death-inducing signaling complex (DISC), followed by activation of effector caspases. TRAIL receptors are composed of death receptors (DR4 and DR5), decoy receptors (DcR1 and DcR2), and osteoprotegerin. Among them, only DRs activate apoptotic signaling by TRAIL. Since the levels of DR expressions are higher in cancer cells than in normal cells, TRAIL selectively activates apoptotic signaling pathway in cancer cells. However, multiple mechanisms, including down-regulation of DR expression and pro-apoptotic proteins, and up-regulation of anti-apoptotic proteins, make cancer cells TRAIL-resistant. Therefore, many researchers have investigated strategies to overcome TRAIL resistance. In this review, we focus on protein regulation in relation to extrinsic apoptotic signaling pathways via ubiquitination. The ubiquitin proteasome system (UPS) is an important process in control of protein degradation and stabilization, and regulates proliferation and apoptosis in cancer cells. The level of ubiquitination of proteins is determined by the balance of E3 ubiquitin ligases and deubiquitinases (DUBs), which determine protein stability. Regulation of the UPS may be an attractive target for enhancement of TRAIL-induced apoptosis. Our review provides insight to increasing sensitivity to TRAIL-mediated apoptosis through control of post-translational protein expression.

• BMB Reports
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• 제56권8호
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• pp.451-456
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• 2023

Deubiquitinases (DUBs) are an essential component of the ubiquitin-proteasome system (UPS). They trim ubiquitin from substrate proteins, thereby preventing them from degradation, and modulate different cellular processes. Ubiquitin-specific protease 14 (USP14) is a DUB that has mainly been studied for its role in tumorigenesis in several cancers. In the present study, we found that the protein levels of USP14 were remarkably higher in gastric cancer tissues than in the adjacent normal tissues. We also demonstrated that the inhibition of USP14 activity using IU1 (an USP14 inhibitor) or the inhibition of USP14 expression using USP14-specific siRNA markedly reduced the viability of gastric cancer cells and suppressed their migratory and invasive abilities. The reduction in gastric cancer cell proliferation due to the inhibition of USP14 activity was a result of the increase in the degree of apoptosis, as evidenced by the increased expression levels of cleaved caspase-3 and cleaved PARP. Furthermore, an experiment using the USP14 inhibitor IU1 revealed that the inhibition of USP14 activity suppressed 5-fluorouracil (5-FU) resistance in GC cells. Collectively, these findings indicate that USP14 plays critical roles in gastric cancer progression and suggest its potential to serve as a novel therapeutic target for gastric cancer treatment.

• 생명과학회지
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• 제26권3호
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• pp.364-375
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• 2016

번역 후 변형 과정은 외부 자극으로부터 세포의 신속한 반응을 야기하는데 있어서 매우 효율적인 기작이다. 이 중, 유비퀴티네이션은 진핵생물 내 대표적인 번역 후 변형 과정으로서, 이러한 유비퀴티네이션에 의해 매개되는 UPS (유비퀴틴/프로테아좀 시스템)는 세포 내 다양한 단백질들의 분해과정을 통해 그들의 안정성을 조절한다. 유비퀴티네이션 과정에 참여하는 3종류의 효소 중에서, E3 효소는 분해할 대상 기질을 결정한다는 면에서 그 중요성을 가지고 있다. CRL (cullin-RING E3 ubiquitin ligase)은 E3 효소 중 가장 거대한 그룹을 형성하고 있는데, 이들은 생체 내에서 cullin, RBX1, 어댑터, 기질 수용체로 이루어진 복합체의 형태로서 그 기능을 발휘한다. 이 중, SCF 복합체로도 알려진 CRL1 복합체의 기능은 다양한 연구를 통해 광범위하게 알려져 온 반면, CRL4 복합체에 대한 연구 및 고찰은 상대적으로 미흡한 실정이다. 또한, 애기장대는 DCAF로 명명된 잠재적 기질 수용체를 총 119개 보유하고 있는데, 현재까지 이들 중 일부 기질 수용체들의 기능만이 밝혀진 상태로서, 나머지 기질 수용체들의 기능 규명은 향후 활발히 탐색되어야 할 연구분야라 할 수 있다. 본 총설에서는 식물의 CRL4 복합체의 구조 및 활성 조절을 알아보고, 각 CRL4 복합체가 관여하는 다양한 식물 내 이벤트에 관하여 최근까지 보고된 CRL4 기질 수용체들을 중심으로 그 연구 진행 사항을 업데이트하고자 한다. 이러한 접근은 각 CRL4 복합체가 기능하는 식물의 다양한 신호 전달 기작들을 보다 명확히 이해하고, 향후 전체 CRL4 복합체의 작용 네트워크를 구축하는데 있어 도움이 될 것으로 사료된다.

• Asian Pacific Journal of Cancer Prevention
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• 제16권9호
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• pp.3723-3727
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• 2015

The p53 tumor suppressor protein is a principal mediator of growth arrest, senescence, and apoptosis in response to a broad array of cellular damage. p53 is a substrate for the ubiquitin-proteasome system, however, the ubiquitin-conjugating enzymes (E2s) involved in p53 ubiquitination have not been well studied. UBE2Q1 is a novel E2 ubiquitin conjugating enzyme gene. Here, we investigated the effect of UBE2Q1 overexpression on the level of p53 in the MDA-MB-468 breast cancer cell line as well as the interaction between UBE2Q1 and p53. By using a lipofection method, the p53 mutated breast cancer cell line, MDA-MB-468, was transfected with the vector pCMV6-AN-GFP, containing UBE2Q1 ORF. Western blot analysis was employed to verify the overexpression of UBE2Q1 in MDA-MB-468 cells and to evaluate the expression level of p53 before and after cell transfection. Immunoprecipitation and GST pull-down protocols were used to investigate the binding of UBE2Q1 to p53. We established MDA-MB-468 cells that transiently expressed a GFP fusion proteins containing UBE2Q1 (GFP-UBE2Q1). Western blot analysis revealed that levels of p53 were markedly lower in UBE2Q1 transfected MDA-MB-468 cells as compared with control MDA-MB-468 cells. Both in vivo and in vitro data showed that UBE2Q1 co-precipitated with p53 protein. Our data for the first time showed that overexpression of UBE2Q1can lead to the repression of p53 in MDA-MB-468 cells. This repression of p53 may be due to its UBE2Q1 mediated ubiquitination and subsequent proteasome degradation, a process that may involve direct interaction of UBE2Q1with p53.

• Molecules and Cells
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• 제39권8호
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• pp.581-586
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• 2016

Post-translational modifications (PTMs) of proteins are essential to increase the functional diversity of the proteome. By adding chemical groups to proteins, or degrading entire proteins by phosphorylation, glycosylation, ubiquitination, neddylation, acetylation, lipidation, and proteolysis, the complexity of the proteome increases, and this then influences most biological processes. Although small RNAs are crucial regulatory elements for gene expression in most eukaryotes, PTMs of small RNA microprocessor and RNA silencing components have not been extensively investigated in plants. To date, several studies have shown that the proteolytic regulation of AGOs is important for host-pathogen interactions. DRB4 is regulated by the ubiquitin-proteasome system, and the degradation of HYL1 is modulated by a de-etiolation repressor, COP1, and an unknown cytoplasmic protease. Here, we discuss current findings on the PTMs of microprocessor and RNA silencing components in plants.

• Asian Pacific Journal of Cancer Prevention
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• 제16권18호
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• pp.8247-8252
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• 2016

Background: The ubiquitin-proteasome system (UPS) degrades a variety of proteins which attach to specific signals. The ubiquitination pathway facilitates degradation of damaged proteins and regulates growth and stress responses. This pathway is altered in various cancers, including acute lymphoblastic leukemia, head and neck squamous cell carcinoma and breast cancer. Recently it has been reported that expression of newly characterized human genes, UBE2Q1 and UBE2Q2, putative members of ubiquitin-conjugating enzyme family (E2), has been also changed in colorectal cancer. Epigenetics is one of the fastest-growing areas of science and nowadays has become a central issue in biological studies of diseases. According to the lack of information about the role of epigenetic changes on gene expression profiling of UBE2Q1 and UBE2Q2, and the presence of CpG islands in the promoter of these two human genes, we decided to evaluate the promoter methylation status of these genes as a first step. Materials and Methods: The promoter methylation status of UBE2Q1 and UBE2Q2 was studied by methylation-specific PCR (MSP) in tumor samples of 60 colorectal cancer patients compared to adjacent normal tissues and 20 non-malignant controls. The frequency of the methylation for each gene was analyzed by chi-square method. Results: MSP results revealed that UBE2Q2 gene promoter were more unmethylated, while a higher level of methylated allele was observed for UBE2Q1 in tumor tissues compared to the adjacent normal tissues and the non malignant controls. Conclusions: UBE2Q1 and UBE2Q2 genes show different methylation profiles in CRC cases.

• Journal of Ginseng Research
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• 제46권2호
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• pp.283-289
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• 2022

Background: Sarcopenia, defined as loss of muscle mass and strength with age, becomes a public health concern as the elderly population increases. This study aimed to determine whether the mixture of soluble whey protein hydrolysate (WPH) and Panax ginseng berry extract (GBE) has a synergetic effect on sarcopenia and, if so, to identify the relevant mechanisms and optimal mixing ratio. Methods: In the first experiment, C57BL/6 mice were hindlimb immobilized for one-week and then administered WPH 800 mg/kg, GBE 100 mg/kg, WPH 800 mg/kg+ GBE 100 mg/kg mixture, and Fructus Schisandrae extract (SFE) 200 mg/kg for two weeks. In the second experiment, experimental design was same, but mice were administered three different doses of WPH and GBE mixture (WPH 800 mg/kg+ GBE 100 mg/kg, WPH 800 mg/kg+ GBE 90 mg/kg, WPH 1000 mg/kg+ GBE 75 mg/kg). Results: In the first experiment, we confirmed the synergetic effect of WPH and GBE on muscle mass and identified that GBE was more effective on the protein synthesis side, and WPH tended to be slightly more effective for protein degradation. In the second experiment, among three different ratios, the WPH 800 mg/kg+ GBE 100 mg/kg was most effective for muscle mass and strength. The mixtures activated muscle protein synthesis via PI3K/Akt/mTORc1 pathway and inhibited muscle protein degradation via suppressing ubiquitin-proteasome system (UPS) and autophagy-lysosome system (ALS), and these effects were more GBE dose-dependent than WPH. Conclusion: The WPH and GBE mixture having a synergetic effect is a potential agent to prevent sarcopenia.