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The deubiquitinase OTUB1 augments NF-κB-dependent immune responses in dendritic cells in infection and inflammation by stabilizing UBC13

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Cellular & Molecular Immunology 2021年第6期18卷 1512-1527页

作者： Floriana Mulas Xu Wang Shanshan Song Gopala Nishanth Wenjing Yi Anna Brunn Pia-Katharina Larsen Berend Isermann Ulrich Kalinke Antonio Barragan Michael Naumann Martina Deckert Dirk Schlüter Institute of Medical Microbiology and Hospital Hygiene Otto-von-Guericke University Magdeburg39120MagdeburgGermany Institute of Medical Microbiology and Hospital Epidemiology Hannover Medical School30625HannoverGermany Chemical biology Research Center School of Pharmaceutical SciencesWenzhou Medical University325035WenzhouChina Department of Neuropathology Faculty of Medicine and University Hospital CologneUniversity of Cologne50931CologneGermany Institute for experimental Infection Research TWINCORE Centre for Experimental and Clinical Infection Researcha joint venture between the Hannover Medical School and the Helmholtz Centre for Infection Research30625HannoverGermany Institute for Clinical Chemistry and Pathobiochemistry Otto-von-Guericke University Magdeburg39120MagdeburgGermany Cluster of Excellence-Resolving Infection Susceptibility(RESIST) Hannover Medical School30625HannoverGermany Department of Molecular Biosciences Stockholm University10691StockholmSweden Institute for experimental Internal Medicine Otto-von-Guericke University Magdeburg39120MagdeburgGermany

Dendritic cells(DCs)are indispensable for defense against pathogens but may also contribute to *** of DCs upon the sensing of pathogens by Toll-like receptors(TLRs)is largely mediated by pattern recognition receptor/nuclear factor-κB(NF-κB)signaling and depends on the appropriate ubiquitination of the respective signaling ***,the ubiquitinating and deubiquitinating enzymes involved and their interactions are only incompletely ***,we reveal that the deubiquitinase OTU domain,ubiquitin aldehyde binding 1(OTUB1)is upregulated in DCs upon murine Toxoplasma gondii infection and lipopolysaccharide *** of DCs with the TLR11/12 ligand *** profilin and the TLR4 ligand lipopolysaccharide induced an increase in NF-κB activation in OTUB1-competent cells,resulting in elevated interleukin-6(IL-6),IL-12,and tumor necrosis factor(TNF)production,which was also observed upon the specific stimulation of TLR2,TLR3,TLR7,and ***,OTUB1 promoted NF-κB activity in DCs by K48-linked deubiquitination and stabilization of the E2-conjugating enzyme UBC13,resulting in increased K63-linked ubiquitination of IRAK1(IL-1 receptor-associated kinase 1)and TRAF6(TNF receptor-associated factor 6).Consequently,DC-specific deletion of OTUB1 impaired the production of cytokines,in particular IL-12,by DCs over the first 2 days of *** infection,resulting in the diminished production of protective interferon-γ(IFN-γ)by natural killer cells,impaired control of parasite replication,and,finally,death from chronic ***,all of which could be prevented by low-dose IL-12 treatment in the first 3 days of *** contrast,impaired OTUB1-deficient DC activation and cytokine production by OTUB1-deficient DCs protected mice from lipopolysaccharide-induced ***,these findings identify OTUB1 as a potent novel regulator of DCs during infectious and inflammatory diseases.

关键词： OTUB1 dendritic cell signal transduction ubiquitination innate immunity

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The tumor-enriched small molecule gambogic amide suppresses glioma by targeting WDR1-dependent cytoskeleton remodeling

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Signal Transduction and Targeted therapy 2023年第12期8卷 5904-5918页

作者： Jiaorong Qu Bojun Qiu Yuxin Zhang Yan Hu Zhixing Wang Zhiang Guan Yiming Qin Tongtong Sui Fan Wu Boyang Li Wei Han Xiaozhong Peng Department of Molecular biology and Biochemistry Institute of Basic Medical SciencesMedical Primate Research CenterNeuroscience CenterChinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China State Key Laboratory of Common Mechanism Research for Major Diseases BeijingChina Department of Molecular Neuropathology Beijing Neurosurgical InstituteCapital Medical UniversityBeijing 100070China Department of Neurosurgery Beijing Tiantan HospitalCapital Medical UniversityBeijingChina State Key Laboratory of Respiratory Health and Multimorbidity BeijingChina National Human Diseases Animal Model Resource Center Beijing Engineering Research Center for Experimental Animal Models of Human Critical DiseasesInstitute of Laboratory Animal ScienceChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100021China

Glioma is the most prevalent brain tumor,presenting with limited treatment options,while patients with malignant glioma and glioblastoma(GBM)have poor *** physical obstacle to drug delivery imposed by the blood‒brain barrier(BBB)and glioma stem cells(GSCs),which are widely recognized as crucial elements contributing to the unsatisfactory clinical *** this study,we found a small molecule,gambogic amide(GA-amide),exhibited the ability to effectively penetrate the blood-brain barrier(BBB)and displayed a notable enrichment within the tumor ***,GA-amide exhibited significant efficacy in inhibiting tumor growth across various in vivo glioma models,encompassing transgenic and primary patient-derived xenograft(PDX)*** further performed a genome-wide clustered regularly interspaced short palindromic repeats(CRISPR)knockout screen to determine the druggable target of *** the combination of the cellular thermal shift assay(CETSA),the drug affinity responsive target stability(DARTS)approach,molecular docking simulation and surface plasmon resonance(SPR)analysis,WD repeat domain 1(WDR1)was identified as the direct binding target of *** direct interaction with WDR1,GA-amide promoted the formation of a complex involving WDR1,MYH9 and Cofilin,which accelerate the depolymerization of F-actin to inhibit the invasion of patient-derived glioma cells(PDCs)and induce PDC apoptosis via the mitochondrial apoptotic *** conclusion,our study not only identified GA-amide as an effective and safe agent for treating glioma but also shed light on the underlying mechanisms of GA-amide from the perspective of cytoskeletal homeostasis.

关键词： glioma invasion homeostasis

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Single-Exosome Profiling Identifies ITGB3+and ITGAM+Exosome Subpopulations as Promising Early Diagnostic Biomarkers and Therapeutic Targets for Colorectal Cancer

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Research 2023年第3期6卷 491-505页

作者： Wei Guo Yanling Cai Xianming Liu Yuge Ji Cuiyu Zhang Liyan Wang Wenting Liao Yuefei Liu Nan Cui Jinsheng Xiang Zesong Li Di Wu Jingxin Li Department of Physiology School of Basic Medical SciencesDepartment of Colorectal SurgeryQilu HospitalCheeloo College of MedicineShandong UniversityJinanShandong250012China Guangdong Provincial Key Laboratory of Systems biology and Synthetic biology for Urogenital tumors Department of UrologyThe First Affiliated Hospital of Shenzhen UniversityShenzhen Second People's Hospital(Shenzhen Institute of Translational Medicine)Shenzhen518035China Shenzhen Key Laboratory of Genitourinary tumor Department of UrologyThe First Affiliated Hospital of Shenzhen UniversityShenzhen Second People's Hospital(Shenzhen Institute of Translational Medicine)Shenzhen518035China Department of Gastrointestinal Surgery Shenzhen People’s HospitalThe Second Clinical Medical College of Jinan UniversityThe First Affiliated Hospital of Southern University of Science and TechnologyShenzhenGuangdong518020China Center for experimental Nuclear Medicine and Electron Microscope School of Basic Medical SciencesShandong UniversityJinanShandong250012China Shenzhen SecreTech Co. Ltd.ShenzhenChina Vesicode AB Nobelsvag 16SolnaSweden

tumor metastasis is a hallmark of colorectal cancer(CRC),in which exosome plays a crucial role with its function in intercellular *** exosomes were collected from healthy control(HC)donors,localized primary CRC and liver-metastatic CRC *** performed proximity barcoding assay(PBA)for single-exosome analysis,which enabled us to identify the alteration in exosome subpopulations associated with CRC *** in vitro and in vivo experiments,the biological impact of these subpopulations on cancer proliferation,migration,invasion,and metastasis was *** potential application of exosomes as diagnostic biomarkers was evaluated in 2 independent validation cohorts by *** distinct exosome subpopulations were *** found 2 distinctly abundant subpopulations:one ITGB3-positive and the other *** ITGB3-positive cluster is rich in liver-metastatic CRC,compared to both HC group and primary CRC *** the contrary,ITGAM-positive exosomes show a large-scale increase in plasma of HC group,compared to both primary CRC and metastatic CRC ***,both discovery cohort and validation cohort verified ITGB3+exosomes as potential diagnostic ***3+exosomes promote proliferation,migration,and invasion capability of *** contrast,ITGAM+exosomes suppress CRC ***,we also provide evidence that one of the sources of ITGAM+exosomes is ***3+exosomes and ITGAM+exosomes are proven 2 potential diagnostic,prognostic,and therapeutic biomarkers for management of CRC.

关键词： invasion metastasis Exosome

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Characterization of calreticulin protein recombinant adenovirus for its anti-tumor function

Characterization of calreticulin protein recombinant adenovi...

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第十一届全国免疫学学术大会

作者： MA Chunling experimental center of Molecular biology Shandong medical college Clinical Test Center Women and Children Hospital of Linyi

Objective: Calreticulin(CRT) has been shown to be highly potent in enhancing the antigen-specific immune responses and antitumor effects induced by inhibiting angiogenesis in several preclinical models. In the current study, we investigated whether CRT, overexpressed by adenovirus, can directly inhibit the growth of tumor ***: The CRT gene was recombined with a p ENTR/D-TOPO transfer vector for construction of a CRT gene recombinant adenoviral expression vector, r Ad-CRT by using the homologous recombination method and was characterized by polymerase chain reaction(PCR), positive clone sequencing. Next, the recombinant rAd-CRT plasmids were transfected into the HEK 293 A cells line to package the recombinant adenovirus and then tittering the adenovirus, rAd-CRT by the limited dilution method. Further, the CRT protein expression levels in MCF-7, MDA-MB-231, and 293 A cells were analyzed via Western blot. Finally, the antitumor function of overexpressed CRT in breast cancer cells was verified by using [3H] Td R ***: The recombinant adenovirus vector, rAd-CRT, was constructed successfully. The CRT protein expression in MCF-7, MDA-MB-231, and 293 A cells was detected by using Western blot specifically. CRT protein overexpressed by adenovirus reduced the proliferation levels of MCF-7 and MDA-MB-231 breast cancer cells directly in contrast to those in control cell ***: Overexpressed CRT can inhibit tumor cell proliferation, directly suppressing the growth of the tumor,which is not associated with the immune mechanism or the inhibition of new-born blood vessels. However, CRT overexpressed in normal cells may not affect their proliferation. This study has provided an experimental basis for the antitumor function of the recombinant adenovirus vector, r Ad-CRT, and laid the foundation for its further investigations in cancer gene therapy.

关键词： Calreticulin Adenovirus Vector breast cancer Cancer gene therapy

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Atypical Atm-p53 genetic interaction in osteogenesis is mediated by Smad1 signaling

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分子细胞生物学报:英文版 2012年第2期4卷 118-120页

作者： Gang Ma Lili Li Yuanyu Hu Jenny Fung Ling Chau Bi Jin Au Deyong Jia Huijuan Liu James Yeh Lin He Aijun Hao Baojie Li The Bio-X Institutes Key Laboratory for the Genetics of Developmental and Neuropsychiatric DisordersMinistry of EducationShanghai Jiao Tong UniversityShanghai 200030China Key Laboratory of the Ministry of Education for experimental Teratology Shandong University School of MedicineJinan 250012China The Institute of Molecular and Cell biology Agency for ScienceTechnologyand ResearchSingapore 138632Singapore

Dear Editor,tumor suppressor p53 is activated in re-sponse to genotoxic stress by Atm and other PI3K-like kinases,which phosphoryl-ate p53 and stabilize p53(Barlow et al.,1997),leading to cell cycle arrest,senes-cence... 详细信息

关键词： Smad1 PI3K damage p53

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Upregulated histamine receptor H3 promotes tumor growth and metastasis in hepatocellular carcinoma

Upregulated histamine receptor H3 promotes tumor growth and ...

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2019年中国肿瘤标志物学术大会暨第十三届肿瘤标志物青...

作者： Zhao,Jing State Key Laboratory of Cancer biology and experimental Teaching Center of Basic Medicine Fourth Military Medical University

Objective Histamine H3 receptors (H3HR) are mostly expressed in the central nervous system,where they are involved in the regulation of the release of various neurotransmitters in the *** studies have shown that the e...

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Site-Specific Selection Reveals Evolutional Constraints and Functionality of tumor Somatic mtDNA Mutations

Site-Specific Selection Reveals Evolutional Constraints and ...

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2017年中国肿瘤标志物学术大会暨第十一届肿瘤标志物青...

作者： Deyang Li Xu guo Chun Yin Jinliang Xing State Key Laboratory of Cancer biology and experimental Teaching Center of Basic Medicine Fourth Military Medical University

Background: Previous studies have indicated that tumor mitochondrial DNA（mtDNA） mutations are primarily shaped by relaxed negative selection, which is contradictory to the critical roles of mtDNA mutations in tumorigenesis. Therefore, we hypothesized that site-specific selection may influence tumor mtDNA mutations. Methods: To test our hypothesis, we developed the largest collection of tumor mtDNA mutations to date and evaluated how natural selection shaped mtDNA mutation patterns. Results: Our data demonstrated that both positive and negative selections acted on specific positions or functional units of tumor mtDNAs, although the landscape of these mutations was consistent with the relaxation of negative selection. In particular, mutation frequencies in complex V and tRNA coding regions, especially in ATP8 within complex V and in loop and variable regions within tRNA, were significantly lower than those in other regions. While the mutation frequencies of most codons and amino acids were consistent with the expectation under neutrality, several codons and amino acids had significantly different frequencies. Moreover, the mutations under selection were enriched for changes that are predicted to be deleterious, further supporting the evolutionary constraints on these regions. Conclusions: In conclusion, these results indicate the existence of site-specific selection and imply the important role of mtDNA mutations in tumor development.

关键词： mtDNA mutation tumorigenesis site-specific selection

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MCUR1-mediated mitochondrial calcium uptake facilitates cell metastasis of hepatocellular carcinoma via the NF-κB depended induction of epithelial-mesenchymal transition

MCUR1-mediated mitochondrial calcium uptake facilitates cell...

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2017年中国肿瘤标志物学术大会暨第十一届肿瘤标志物青...

作者：王娇娇任婷婷邢金良 State Key Laboratory of Cancer biology and experimental Teaching Center of Basic Medicine Fourth Military Medical University

Aims: Levels of the Mitochondrial Calcium uniporter regulator 1(MCUR1) increases during development of hepatocellular carcinoma(HCC). However, mechanistic understanding of how mitochondrial Ca2+ homeostasis is remodeled and its functional roles remains limited in cancers, especially in HCC. Methods and Results: MCUR1 was frequently upregulated in HCC cells to enhance the Ca2+ uptake into mitochondria in a MCU-dependent manner, which significantly facilitated cell metastasis, and thus contributed to poor prognosis of HCC patients. In vivo assay confirmed these results, indicating that forced expression of MCUR1 significantly increased the ability of invasion and migration in vitro and intrahepatic and distal lung metastasis, while decreased MCUR1 expression was associated with impaired metastasis capacity of HCC cells in nude mice. The increased ability of metastasis conferred by MCUR1-mediated mitochondrial Ca2+ uptake was majorly caused by the activated NF-κB signaling which induced EMT progression of HCC cells. In addition, treatment with mitochondrial Ca2+-buffering protein parvalbumin significantly suppressed ability of HCC metastasis. Conclusion: Our study provides evidence supporting a possible tumor-promoting role for MCUR1-mediated mitochondrial Ca2+ uptake and uncovers a mechanism that links remodeling of mitochondrial Ca2+ homeostasis to cancer cell metastasis. Our findings suggest that mitochondrial Ca2+ uptake machinery may potentially be a novel therapeutic target for HCC metastasis.

关键词： Mitochondrial Ca2+ mitochondrial calcium uniporter regulator 1 hepatocellular carcinoma metastasis NF-κB EMT

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The mechanism and biological significance of aberrant expression of non-coding telomeric repeat-containing RNA in hepatocellular carcinoma

The mechanism and biological significance of aberrant expres...

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2017年中国肿瘤标志物学术大会暨第十一届肿瘤标志物青...

作者：曹海燕王姣姣任婷婷邢金良 State Key Laboratory of Cancer biology and experimental Teaching Center of Basic Medicine Fourth Military Medical University

Background and Aims: Abnormal changes of telomere length are associated with the occurrence and progression of tumor. How the occurrence and progression of hepatocellular carcinoma（HCC） influenced by telomere RNA and what the biological significance based on this mechanism remained largely unknown. Results and Methods: Our data showed that telomeric repeat-containing RNA（TERRA） is frequently downregulated in HCC and correlated with subtelomeric DNA methylation *** the same time, we found that TERRA plays a negative role in proliferation of HCC cells by EdU and MTS,and downregulation of TERRA promotes HCC cell apoptosis by flow cytometry in vitro. We also found that downregulation of TERRA inhibits tumor metastasis and tumor growth respectively by orthotopic hepatic tumor formation and subcutaneous tumor formation in nude ***, We demonstrated that downregulation of TERRAsignificantly promotes the survival and inhibits metastasis of HCC cells via p53/Rb/E2 F pathway. Conclusions: Our findings demonstrate that TERRAplays a critical role in the regulation of HCC cells survival and metastasis, and provides strong evidence for this process as a drug target in HCC treatment.

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Mining Gene Expression Profiles:An Integrated Implementation of Kernel Principal Component Analysis and Singular Value Decomposition

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Genomics, Proteomics & Bioinformatics 2010年第3期8卷 200-210页

作者： Ferran Reverter Esteban Vegas Pedro Sánchez Department of Statistics Faculty of BiologyUniversity of Barcelona

The detection of genes that show similar profiles under different experimental conditions is often an initial step in inferring the biological significance of such genes. Visualization tools are used to identify genes with similar profiles in microarray studies. Given the large number of genes recorded in microarray experiments, gene expression data are generally displayed on a low dimensional plot, based on linear methods. However, microarray data show nonlinearity, due to high-order terms of interaction between genes, so alternative approaches, such as kernel methods, may be more appropriate. We introduce a technique that combines kernel principal component analysis （KPCA） and Biplot to visualize gene expression profiles. Our approach relies on the singular value decomposition of the input matrix and incorporates an additional step that involves KPCA. The main properties of our method are the extraction of nonlinear features and the preservation of the input variables （genes） in the output display. We apply this algorithm to colon tumor, leukemia and lymphoma datasets. Our approach reveals the underlying structure of the gene expression profiles and provides a more intuitive understanding of the gene and sample association.

关键词： kernel method biplot gene expression profile dimension reduction

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