The Experts below are selected from a list of 39213 Experts worldwide ranked by ideXlab platform
Daxiang Cui - One of the best experts on this subject based on the ideXlab platform.
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usp22 maintains gastric cancer stem cell stemness and promotes gastric cancer progression by stabilizing BMI1 Protein
Oncotarget, 2017Co-Authors: Zhen Wang, Hai Huang, Jie Song, Ying Xia, Weilin Jin, Daxiang CuiAbstract:// Yue Ma 1, 2 , Hua-Lin Fu 1, 3 , Zhen Wang 4 , Hai Huang 5 , Jian Ni 1, 3 , Jie Song 1, 3 , Ying Xia 5 , Wei-Lin Jin 1, 3 and Da-Xiang Cui 1, 2, 3 1 Institute of Nano Biomedicine and Engineering, Shanghai Engineering Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, Key Laboratory for Thin Film and Microfabrication Technology of Ministry of Education, School of Electronic Information and Electronic Engineering, Shanghai Jiao Tong University, Shanghai 200240, China 2 School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China 3 National Center for Translational Medicine, Collaborative Innovational Center for System Biology, Shanghai Jiao Tong University, Shanghai 200240, China 4 Center for Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi’an Jiao Tong University, Xi’an 710049, China 5 Department of Clinical Biochemistry, School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou 550005, China Correspondence to: Wei-Lin Jin, email: weilinjin@sjtu.edu.cn Da-Xiang Cui, email: dxcui@sjtu.edu.cn Keywords: USP22, BMI1, gastric cancer stem cell, gastric cancer, deubiquitinase Received: December 15, 2016 Accepted: March 09, 2017 Published: March 22, 2017 ABSTRACT Increased ubiquitin-specific protease 22 (USP22) has been associated with poor prognosis in several cancers including gastric cancer. However, the role of USP22 in gastric tumorigenesis is still unclear. Gastric cancer stem cells have been identified and shown to correlate with gastric cancer initiation and metastasis. In this study, we found that silencing of USP22 inhibited proliferation of gastric cancer cells and suppressed the cancer stem cell spheroid formation in serum-free culture. Furthermore, cancer stem cell markers, such as CD133, SOX2, OCT4 and NANOG were down-regulated. Additionally, knockdown of USP22 inhibited gastric cancer xenografts growth. Our analysis of TCGA database indicated that BMI1 overexpression may predict gastric cancer patient survival, and TAT-BMI1 Proteins reversed the USP22 knockdown-mediated decreased in cancer stem cell properties, and elevated the expression of stemness-associated genes. Furthermore, we found that overexpression of USP22 stabilized the BMI1 Protein in gastric cancer cells. Taken together, our study demonstrates that USP22 is indispensable for gastric cancer stem cell self-renewal through stabilization of BMI1. These results may provide novel approaches to the theranostics of gastric cancer in the near future.
Neil Gregory Almstead - One of the best experts on this subject based on the ideXlab platform.
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abstract 2528 optimization of small molecules targeting BMI1 Protein expression part 2 improved potency oral bioavailability and in vivo efficacy of amino pyrazines and amino pyridines
Cancer Research, 2014Co-Authors: Ramil Baiazitov, Liangxian Cao, Nadiya Sydorenko, Chang-sun Lee, Thomas W. Davis, Hongyu Ren, Steve Paget, Richard Gerald Wilde, Ronggang Liu, Neil Gregory AlmsteadAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Earlier, in our efforts to identify molecules that selectively deplete tumor stem cells, we discovered and elaborated on a series of amino-thiazoles. These first-in-class small molecule inhibitors reduce the activity and levels of BMI1 Protein in vitro and in vivo (see the preceding poster). Through our medicinal chemistry efforts, we developed a second generation of molecules that reduce levels of BMI1. In this new scaffold, the central thiazole ring has been replaced with a pyrazine or pyridine ring. There is a clear relationship between the structure of the central heterocycle and the ability of the compound to decrease the level of BMI1 Protein. The most beneficial modification on the right wing of the molecule is the introduction of benzimidazole moiety. As a result, analogs with markedly improved oral bioavailability have been identified. The structure activity relationship on the left ring parallels the SAR observed with the amino-thiazole scaffold. The most successful analogs in this series can be dosed orally and demonstrate dose-dependent efficacy in mouse xenograft models including the HT1080 and L1210 cell lines. Citation Format: Ramil Baiazitov, Nadiya Sydorenko, Hongyu Ren, Wu Du, Steve Paget, Richard Wilde, Ronggang Liu, Chang-Sun Lee, Liangxian Cao, Thomas W. Davis, Neil G. Almstead, Young-Choon Moon. Optimization of small molecules targeting BMI1 Protein expression. Part 2. Improved potency, oral bioavailability, and in vivo efficacy of amino-pyrazines and amino-pyridines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2528. doi:10.1158/1538-7445.AM2014-2528
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Abstract 2529: Optimization of small molecules targeting BMI1 Protein expression. Part 1. Amino-thiazoles: the first-in-class highly potent inhibitors of BMI1 Protein
Cancer Chemistry, 2014Co-Authors: Nadiya Sydorenko, Liangxian Cao, Ramil Baiazitov, Soongyu Choi, Chang-sun Lee, Thomas W. Davis, Neil Gregory Almstead, Young-choon MoonAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA BMI1 (B-cell specific Moloney Murine Leukemia Virus Insertion 1) is a gene predominantly expressed in stem cells. A deficiency of BMI1 Protein leads to a reduction in the adult stem cell population. Decreasing of BMI1 Protein levels by siRNA causes apoptosis and/or senescence in tumor cells in vitro and increases susceptibility to cytotoxic agents. In tumors, the level of BMI1 Protein is often elevated. Consequently, the expression level of BMI1 is highly prognostic in many types of cancers. Since BMI1 is non-enzymatic, targeting this Protein by traditional drug discovery approaches has not met with success. PTC Therapeutics has developed a novel screening technology referred to as GEMSTM (Gene Expression Modulation by Small molecules) to identify small molecules that modulate the levels of a Protein of interest by targeting post-transcriptional regulatory processes. Using this screening technology, we have identified a number of compounds that can selectively reduce levels of BMI1 Protein. Schematically, the lead scaffold could be represented by four key components: a bicyclic right core, a heterocyclic middle ring (thiazole), a linking group and a left aryl region. Structure-activity relationships associated with this series have been investigated through medicinal chemistry efforts. Incorporation of a small electron-donating para- substituent at the left part of the molecule is highly effective in decreasing levels of BMI1, indicating the strong influence of both steric and electronic effects on activity. An amino (linking group) moiety was found to be essential for activity. Variation at the right-hand moiety appears to be more tolerated, allowing improvements in both pharmacokinetic and activity profiles. These SAR findings have revealed important pharmacophoric and structural features required for the desired biological activity with this series, and provide a foundation for further lead optimization efforts. Citation Format: Nadiya Sydorenko, Ramil Baiazitov, Soongyu Choi, Chang-Sun Lee, Liangxian Cao, Thomas W. Davis, Neil G. Almstead, Young-Choon Moon. Optimization of small molecules targeting BMI1 Protein expression. Part 1. Amino-thiazoles: the first-in-class highly potent inhibitors of BMI1 Protein. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2529. doi:10.1158/1538-7445.AM2014-2529
Marina Montali - One of the best experts on this subject based on the ideXlab platform.
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the polycomb BMI1 Protein is co expressed with cd26 in leukemic stem cells of chronic myeloid leukemia
Frontiers in Oncology, 2018Co-Authors: Sara Galimberti, Susanna Grassi, Claudia Barate, Francesca Guerrini, Elena Ciabatti, Francesca Perutelli, Federica Ricci, Giada Del Genio, Marina MontaliAbstract:The Polycomb gene BMI1 expression exerts a negative predictive impact on several hematological malignancies, such as acute and chronic myeloid leukemia (CML), myelofibrosis, and follicular lymphoma. As already demonstrated in CML, BMI1 is responsible for the resistance to the tyrosine kinase inhibitors (TKIs) in a BCR-ABL1-independent way. Even if, it is unknown where BMI1 in CML is expressed (in progenitors or more mature cells). We decided, therefore, to evaluate if and where the BMI1 Protein is located, focusing mainly on the CD34+/CD38-/CD26+ CML progenitors. To begin we measured, by flow cytometry, the proportion of CD34+/CD26+ cells in 31 bone marrow samples from 20 CML patients, at diagnosis and during treatment with imatinib. After that the bone marrow blood smears were stained with antibodies anti-CD26, BCR-ABL1, and BMI1. These smears were observed by a confocal laser microscope and a 3D reconstruction was then performed. At diagnosis, CD34+/CD26+ cells median value/μL was 0.48; this number increased from diagnosis to the third month of therapy and then reduced during treatment with imatinib. The number and behavior of the CD26+ progenitors were independent from the BCR-ABL1 expression, but they summed up what previously observed about the BMI1 expression modulation. In this work we demonstrate for the first time that in CML the BMI1 Protein is co-expressed with BCR-ABL1 only in the cytoplasm of the CD26+ precursors; on the contrary, in other hematological malignancies where BMI1 is commonly expressed (follicular lymphoma, essential thrombocytemia, acute myeloid leukemia), it was not co-localized with CD26 or, obviously, with BCR-ABL1. Once translated into the clinical context, if BMI1 is a marker of stemness, our results would suggest the combination of the BMI1 inhibitors with TKIs as an interesting object of research, and, probably, as a promising way to overcome resistance in CML patients.
Maarten Van Lohuizen - One of the best experts on this subject based on the ideXlab platform.
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chromatin association of the polycomb group Protein BMI1 is cell cycle regulated and correlates with its phosphorylation status
Journal of Cell Science, 1999Co-Authors: Jan Willem Voncken, Laurra Aagaard, Linda Sattler, Michael F Jantsch, D Schweizer, Maarten Van LohuizenAbstract:The human proto-oncogene BMI1 is a member of the mammalian Polycomb Group (Pc-G) genes. The subnuclear distribution of the BMI1 Protein was studied in several primary human and tumor-derived cell lines using immunohistochemical and biochemical methods. In primary and tumor cells, nuclear BMI1 shows a fine-grain distribution over chromatin, usually dense in interphase nuclei and significantly weaker along mitotic chromosomes. In addition, BMI1 preferentially associates with several distinct heterochromatic domains in tumor cell lines. In both primary and tumor cell lines a marked cell cycle-regulation of Pc-G-chromatin interaction is observed: nuclear BMI1-staining dissipates in late S phase and is re-established early in G(1)-phase. Chromatin-association of BMI1 inversely correlates with its phosphorylation status in a cell cycle-dependent fashion: at G(1)/S, hypophosphorylated BMI1 is specifically retained in the chromatin-associated nuclear Protein fraction, whereas during G(2)/M, phosphorylated BMI1 is not chromatin-bound. Our findings indicate a strict cell cycle-controlled regulation of Pc-G complex-chromatin association and provide molecular tools for improving our understanding of Pc-G complex regulation and function in mammalian cells.
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pertubation of b and t cell development and predisposition to lymphomagenesis in emu BMI1 transgenic mice require the BMI1 ring finger
Oncogene, 1997Co-Authors: Heinz Jacobs, Maarten Van Lohuizen, Mark J Alkema, Anton BernsAbstract:Proviral activation of the BMI1 gene has implicated BMI1 as a collaborator of c-Myc in lymphomagenesis. To determine the effect of BMI1 overexpression on hema- topoiesis and lymphomagenesis transgenic mice were generated that overexpress different forms of the BMI1 Protein in their lymphoid compartment. EμBMI1 transgenic mice, overexpressing the wild type BMI1 Protein showed a perturbed lymphoid development and were highly susceptible to B and T cell lymphomagenesis. Mutational analysis of the BMI1 Protein demonstrated that the conserved N-terminal RING finger and central part of BMI1 are essential for its oncogenic potential whereas the C-terminal Pro-Ser rich region is not required. We have used provirus tagging in the EμBMI1 mice to identify genes that cooperate with BMI1 in lymphomagenesis. MoMLV infection in EμBMI1 transgenic mice accelerated lymphoma development. Proviral activation of the Pim and Myc genes but not the Gfi1 gene were frequently observed in these tumors. These results demonstrate that BMI1 is a potent oncogene and suggest that it plays an important role in early lymphoid development.
Susanna Grassi - One of the best experts on this subject based on the ideXlab platform.
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the polycomb BMI1 Protein is co expressed with cd26 in leukemic stem cells of chronic myeloid leukemia
Frontiers in Oncology, 2018Co-Authors: Sara Galimberti, Susanna Grassi, Claudia Barate, Francesca Guerrini, Elena Ciabatti, Francesca Perutelli, Federica Ricci, Giada Del Genio, Marina MontaliAbstract:The Polycomb gene BMI1 expression exerts a negative predictive impact on several hematological malignancies, such as acute and chronic myeloid leukemia (CML), myelofibrosis, and follicular lymphoma. As already demonstrated in CML, BMI1 is responsible for the resistance to the tyrosine kinase inhibitors (TKIs) in a BCR-ABL1-independent way. Even if, it is unknown where BMI1 in CML is expressed (in progenitors or more mature cells). We decided, therefore, to evaluate if and where the BMI1 Protein is located, focusing mainly on the CD34+/CD38-/CD26+ CML progenitors. To begin we measured, by flow cytometry, the proportion of CD34+/CD26+ cells in 31 bone marrow samples from 20 CML patients, at diagnosis and during treatment with imatinib. After that the bone marrow blood smears were stained with antibodies anti-CD26, BCR-ABL1, and BMI1. These smears were observed by a confocal laser microscope and a 3D reconstruction was then performed. At diagnosis, CD34+/CD26+ cells median value/μL was 0.48; this number increased from diagnosis to the third month of therapy and then reduced during treatment with imatinib. The number and behavior of the CD26+ progenitors were independent from the BCR-ABL1 expression, but they summed up what previously observed about the BMI1 expression modulation. In this work we demonstrate for the first time that in CML the BMI1 Protein is co-expressed with BCR-ABL1 only in the cytoplasm of the CD26+ precursors; on the contrary, in other hematological malignancies where BMI1 is commonly expressed (follicular lymphoma, essential thrombocytemia, acute myeloid leukemia), it was not co-localized with CD26 or, obviously, with BCR-ABL1. Once translated into the clinical context, if BMI1 is a marker of stemness, our results would suggest the combination of the BMI1 inhibitors with TKIs as an interesting object of research, and, probably, as a promising way to overcome resistance in CML patients.