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Effects of inhibition of ubiquitin-proteasome pathway on human primary leukemic cells

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Science China(Life Sciences) 2002年第6期45卷 647-654页

作者：兰雨张学敏杨平地胡美茹于鸣杨怡沈倍奋 Institute of Basic Medical Sciences Beijing 100850 China Instrumental Analysis Center Beijing 100850 China Department of Hematology Yanjing Hospital Beijing 100037 China

Though there were a lot of reports about the totally different responses to the inhibition of ubiquitin-proteasome pathway in different kinds of cell lines, much less has been known about the responses in primary human leukemic cells. In this study, the effects of inhibition of ubiquitin-proteasome pathway on human bone marrow (BM) mononuclear cells (MNCs) obtained from 10 normal persons and 8 leukemia patients were examined. The results showed that the responses obviously varied individually. Among them, BM MNCs in 3 cases of leukemic patients were extremely sensitive, demonstrated by that >90% cells were induced to undergo apoptosis within 24 h, but MNCs in 10 cases of normal persons showed resistance to the inhibition and no apoptosis was observed. Furthermore, Western blots revealed that the Bcl-2 expression was relatively high in the sensitive primary leukemia cells, and especially the cleavage of 26 ku Bcl-2 into a 22 ku fragment occurred during the induction of apoptosis. In contrast, the Bcl-2 expression was either undetectable or detectable but no cleavage of that above was observed in the cells insensitive to the inhibition of the pathway (including BM MNCs in normal persons). Together with the observations on the leukemic cell lines, these findings suggested the correlation of the specific cleavage of Bcl-2 into a shortened fragment with the sensitivity of cells to the inhibition of ubiquitin-proteasome pathway, which provides clues to the further understanding of the mechanisms of that dramatically different responses existing in different kinds of cells to the inhibition of ubiquitin-proteasome pathway.

关键词： ubiquitin-proteasome pathway, primary leukemic cells, apoptosis, Bcl-2.

Degradation of proteins by PROTACs and other strategies

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Acta Pharmaceutica Sinica B 2020年第2期10卷 207-238页

作者： Yang Wang Xueyang Jiang Feng Feng Wenyuan Liu Haopeng Sun Department of Pharmaceutical Analysis Key Laboratory of Drug Quality Control and PharmacovigilanceMinistry of EducationChina Pharmaceutical UniversityNanjing 210009China Department of Natural Medicinal Chemistry China Pharmaceutical UniversityNanjing 211198China Jiangsu Food and Pharmaceutical Science College Huaian 223003 China Department of Medicinal Chemistry China Pharmaceutical UniversityNanjing 211198China

Abnormal protein expression or activities are associated with many diseases,especially cancer.Therefore,down-regulating the proteins involved in cancer cell survival proved to be an effective strategy for cancer treatment—a number of drugs based on proteolysis-targeting chimaera(PROTAC)mechanism have demonstrated clinical efficacy.Recent progress in the PROTAC strategy includes identification of the structure of the first ternary eutectic complex,extra-terminal domain-4-PROTAC-VonHippel-Lindau(BRD4-PROTAC-VHL),and PROTAC ARV-110 has entered clinical trials for the treatment of prostate cancer in 2019.These discoveries strongly proved the value of the PROTAC strategy.In this review,we summarize recent meaningful research of PROTACs,including the molecular design and optimization strategy as well as clinical application of candidate molecules.We hope to provide useful insights for rational design of PROTACs.

关键词： Protein degradation PROTAC ubiquitin-proteasome system E3 ubiquitin ligase Target protein Heterobifunctional molecule

Effects of ubiquitin-protea-some pathway on mouse sperm capacitation, acrosome reaction and in vitro fertilization

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Chinese Science Bulletin 2002年第2期47卷 127-132页

作者： WANG Hongmei SONG Changcheng DUAN Chongwen SHI Weixian LI Cunxi CHEN Dayuan WANG Yongchao State Key Laboratory of Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100080China Institute of Cell Biology College of Life SciencesBeijing Normal UniversityBeijing 100875China

Chlortetracycline (CTC) fluorescence patterns were used to study changes in the patterns B and AR of mouse sperm after incubation with reagents that would block the UPP. They were the monoclonal antibody againstubiquitinated proteins——UCPi; the polyclonal antibodyagainst ubiquitin-anti-Ub, and a special inhibitor againstproteasome——ALLN. Furthermore, we treated the capaci-tated sperm or the eggs with these reagents separately and tested whether the normal in vitro fertilization was blocked or not. Results illustrate that UCP1, anti-Ub, and ALLN have little effects on sperm capacitation and acrosome reaction, but they do inhibit fusion of mouse sperm with eggs, which suggests that UPP play an important role in mouse in vitro fertilization.

关键词： ubiquitin-proteasome pathway capacitation acrosome reaction in vitro fertilization.

IGF-1 promotes the growth and metastasis of hepatocellular carcinoma via the inhibition of proteasome-mediated cathepsin B degradation

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World Journal of Gastroenterology 2015年第35期21卷 10137-10149页

作者： Tian Lei Xie Ling Department of Gastroenterology the First Affiliated Hospital of Liaoning Medical University Department of Anatomy Liaoning Medical College

AIM: To investigate the molecular mechanisms of the high IGF-1 level linking diabetes and cancers, which is a risk factor.METHODS: We used cell growth, wound healing and transwell assay to evaluate the proliferation and metastasis ability of the hepatocellular carcinoma(HCC) cells. Western blot and reverse transcription polymerase chain reaction were used to assess a previously identified lysosomal protease, cathepsin B(CTSB) expression in the HCC cell lines. C57 BL/6J and KK-Ay diabetic mice are used to detect the growth and metastasis of HCC cells that were depleted with or without CTSB sh RNA in vivo. Statistical significance was determined by Student's t-test.RESULTS: IGF-1 promoted the growth and metastasis of the HCC cell lines via its ability to enhance CTSB expression in both a time-dependent and concentration-dependent manner. HCC cells grew much faster in diabetic KK-Ay mice than in C57 BL/6J mice. Additionally, more metastatic nodules were found in the lungs of KK-Ay mice than the lungs of C57 BL/6J mice. CTSB depletion protects against the tumorpromoting actions of IGF-1 in HCC cells, as well tumor growth and metastasis both in vitro and in vivo.IGF-1 did not change the m RNA levels of CTSB but prolonged the half-life of cathepsin B in Hepa 1-6 and H22 cells. Our results showed that IGF-1 promotes the growth and metastasis of the HCC cells most likely by hindering CTSB degradation mediated by the ubiquitinproteasome system(UPS), but not autophagy. Overexpression of proteasome activator 28, a family of activators of the 20 S proteasome, could not only restore IGF-1-inhibited UPS activity but also decrease IGF-1-induced CTSB accumulation.CONCLUSION: Our study demonstrates that IGF-1 promotes the growth and metastasis of hepatocellular carcinoma by inhibition of proteasome-mediated CTSB degradation.

关键词： IGF-1 Cathepsin B ubiquitin-proteasome system Hepa

ubiquitin-conjugating enzyme involved in the immune response caused by pathogens invasion

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Open Journal of Immunology 2013年第3期3卷 93-97页

作者： Liang Chen Chen Cheng Chunxia Zhang Qin Yao Ermi Zhao Institute of Life Sciences Jiangsu University Zhenjiang China Key Laboratory of Bio-Resources and Eco-Environment College of Life Sciences Sichuan University Chengdu China

ubiquitin-proteasome pathway (UPP) is a significant way of protein degradation and modification in eukaryotic cell and involved in a complex series of intracellular processes. As a key component in UPP,?ubiquitin-conjugating enzyme (E2) plays an extremely important role in ubiquitin (Ub) transferring and substrate specific recognition. Abundant evidences have proved that UPP is involved in cells immune reaction caused by pathogens and the attendance of E2 has a significant effect on host cells and pathogen. This article presents an overview of the current research on E2s that is involved in immune response caused by viruses and bacteria.

关键词： ubiquitin-Conjugating Enzyme ubiquitin-proteasome Pathway Pathogen Immune Response

The regulating effect of Cullin-RING E3 ligase in the passway of abiotic stresses

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The regulating effect of Cullin-RING E3 ligase in the passwa...

Isoflurane preconditioning induces neuroprotection by attenuating ubiquitin-conjugated protein aggregation after transient global cerebral ischemia in mouse

2013全国植物生物学大会

作者： GUO Liquan WU Ming Key Laboratory of Grain and Oil Processing of Jilin Province Jilin Business and Technology College State Environmental Protection Key Laboratory of Wetland Ecology and Vegetation Restoration Northeast Normal University

Cullin-RING(CRL)complexes in ubiquitin-proteasome system play important roles in plants responding to various abiotic stresses in this article.Especially,RING E3 ligase and U-boxE3 s related to regula

关键词： ubiquitin-proteasome system Cullin-RING E3 ligase abiotic stresses

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Isoflurane preconditioning induces neuroprotection by attenu...