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  1. Article ; Online: Force-dependent trans-endocytosis by breast cancer cells depletes costimulatory receptor CD80 and attenuates T cell activation.

    Park, Seungman / Shi, Yu / Kim, Byoung Choul / Jo, Myung Hyun / Cruz, Leilani O / Gou, Zheming / Ha, Taekjip / Lu, Li-Fan / Reich, Daniel H / Chen, Yun

    Biosensors & bioelectronics

    2020  Volume 165, Page(s) 112389

    Abstract: In this study, we investigated the biophysical interaction between cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and CD80. CTLA-4 is a key molecule in immunosuppression, and CD80 is a costimulatory receptor promoting T cell activation. We observed ...

    Abstract In this study, we investigated the biophysical interaction between cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and CD80. CTLA-4 is a key molecule in immunosuppression, and CD80 is a costimulatory receptor promoting T cell activation. We observed that after cell-cell contact was established between breast cancer cells and antigen presenting cells (APCs), CTLA-4 expressed on the breast cancer cells bind to CD80 expressed on the APCs, and underwent trans-endocytosis to deplete CD80. Force measurement and live cell imaging revealed that upon binding to CD80, forces generated by breast cancer cells and transmitted via CTLA-4 were sufficiently strong to displace CD80 from the surface of APCs to be internalized by breast cancer cells. We further demonstrated that because of the force-dependent trans-endocytosis of CD80, the capacity of APCs to activate T cells was significantly attenuated. Furthermore, inhibiting force generation in cancer cells would increase the T cell activating capacity of APCs. Our results provide a possible mechanism behind the immunosuppression commonly seen in breast cancer patients, and may lead to a new strategy to restore anti-tumor immunity by inhibiting pathways of force-generation.
    MeSH term(s) B7-2 Antigen ; Biosensing Techniques ; Breast Neoplasms ; CD28 Antigens ; Endocytosis ; Humans ; Lymphocyte Activation ; T-Lymphocytes
    Chemical Substances B7-2 Antigen ; CD28 Antigens
    Language English
    Publishing date 2020-06-17
    Publishing country England
    Document type Journal Article
    ZDB-ID 1011023-9
    ISSN 1873-4235 ; 0956-5663
    ISSN (online) 1873-4235
    ISSN 0956-5663
    DOI 10.1016/j.bios.2020.112389
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    In stock of ZB MED Cologne/Königswinter

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  2. Article ; Online: Excessive expression of miR-27 impairs Treg-mediated immunological tolerance.

    Cruz, Leilani O / Hashemifar, Somaye Sadat / Wu, Cheng-Jang / Cho, Sunglim / Nguyen, Duc T / Lin, Ling-Li / Khan, Aly Azeem / Lu, Li-Fan

    The Journal of clinical investigation

    2017  Volume 127, Issue 2, Page(s) 530–542

    Abstract: MicroRNAs (miRs) are tightly regulated in the immune system, and aberrant expression of miRs often results in hematopoietic malignancies and autoimmune diseases. Previously, it was suggested that elevated levels of miR-27 in T cells isolated from ... ...

    Abstract MicroRNAs (miRs) are tightly regulated in the immune system, and aberrant expression of miRs often results in hematopoietic malignancies and autoimmune diseases. Previously, it was suggested that elevated levels of miR-27 in T cells isolated from patients with multiple sclerosis facilitate disease progression by inhibiting Th2 immunity and promoting pathogenic Th1 responses. Here we have demonstrated that, although mice with T cell-specific overexpression of miR-27 harbor dysregulated Th1 responses and develop autoimmune pathology, these disease phenotypes are not driven by miR-27 in effector T cells in a cell-autonomous manner. Rather, dysregulation of Th1 responses and autoimmunity resulted from a perturbed Treg compartment. Excessive miR-27 expression in murine T cells severely impaired Treg differentiation. Moreover, Tregs with exaggerated miR-27-mediated gene regulation exhibited diminished homeostasis and suppressor function in vivo. Mechanistically, we determined that miR-27 represses several known as well as previously uncharacterized targets that play critical roles in controlling multiple aspects of Treg biology. Collectively, our data show that miR-27 functions as a key regulator in Treg development and function and suggest that proper regulation of miR-27 is pivotal to safeguarding Treg-mediated immunological tolerance.
    MeSH term(s) Animals ; Cell Differentiation/genetics ; Cell Differentiation/immunology ; Gene Expression Regulation/immunology ; Immune Tolerance ; Mice ; Mice, Transgenic ; MicroRNAs/genetics ; MicroRNAs/immunology ; T-Lymphocytes, Regulatory/immunology ; Th1 Cells/immunology ; Th2 Cells/immunology
    Chemical Substances MicroRNAs ; Mirn27 microRNA, mouse
    Language English
    Publishing date 2017-02-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI88415
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  3. Article ; Online: MiR-23~27~24-mediated control of humoral immunity reveals a TOX-driven regulatory circuit in follicular helper T cell differentiation.

    Wu, Cheng-Jang / Cho, Sunglim / Huang, Hsi-Yuan / Lu, Chun-Hao / Russ, Jasmin / Cruz, Leilani O / da Cunha, Flavia Franco / Chen, Mei-Chi / Lin, Ling-Li / Warner, Lindsey M / Liao, Hsin-Kai / Utzschneider, Daniel T / Quon, Sara / Berner, Jacqueline / Camara, Niels Olsen Saraiva / Zehn, Dietmar / Belmonte, Juan Carlos Izpisua / Chen, Li-Chen / Huang, Shiang-Fu /
    Kuo, Ming-Ling / Lu, Li-Fan

    Science advances

    2019  Volume 5, Issue 12, Page(s) eaaw1715

    Abstract: Follicular helper T ( ... ...

    Abstract Follicular helper T (T
    MeSH term(s) Animals ; Cell Differentiation/genetics ; Gene Expression Regulation, Developmental/immunology ; High Mobility Group Proteins/genetics ; Humans ; Immunity, Humoral/genetics ; Immunity, Humoral/immunology ; Lymphocyte Activation/immunology ; Mice ; MicroRNAs/genetics ; Proto-Oncogene Proteins c-bcl-6/genetics ; Signal Transduction ; T-Lymphocytes/immunology ; T-Lymphocytes, Helper-Inducer/immunology ; T-Lymphocytes, Helper-Inducer/metabolism
    Chemical Substances BCL6 protein, human ; High Mobility Group Proteins ; MicroRNAs ; Mirn23b microRNA, mouse ; Mirn24 microRNA, mouse ; Mirn27 microRNA, mouse ; Proto-Oncogene Proteins c-bcl-6 ; TOX protein, human
    Language English
    Publishing date 2019-12-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2810933-8
    ISSN 2375-2548 ; 2375-2548
    ISSN (online) 2375-2548
    ISSN 2375-2548
    DOI 10.1126/sciadv.aaw1715
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  4. Article ; Online: Kinesin-14 Pkl1 targets γ-tubulin for release from the γ-tubulin ring complex (γ-TuRC) ‬‬‬‬‬‬‬.

    Olmsted, Zachary T / Riehlman, Timothy D / Branca, Carmen N / Colliver, Andrew G / Cruz, Leilani O / Paluh, Janet L

    Cell cycle (Georgetown, Tex.)

    2013  Volume 12, Issue 5, Page(s) 842–848

    Abstract: The γ-tubulin ring complex (γ-TuRC) is a key part of microtubule-organizing centers (MTOCs) that control microtubule polarity, organization and dynamics in eukaryotes. Understanding regulatory mechanisms of γ-TuRC function is of fundamental importance, ... ...

    Abstract The γ-tubulin ring complex (γ-TuRC) is a key part of microtubule-organizing centers (MTOCs) that control microtubule polarity, organization and dynamics in eukaryotes. Understanding regulatory mechanisms of γ-TuRC function is of fundamental importance, as this complex is central to many cellular processes, including chromosome segregation, fertility, neural development, T-cell cytotoxicity and respiration. The fission yeast microtubule motor kinesin-14 Pkl1 regulates mitosis by binding to the γ-tubulin small complex (γ-TuSC), a subunit of γ-TuRC. Here we investigate the binding mechanism of Pkl1 to γ-TuSC and its functional consequences using genetics, biochemistry, peptide assays and cell biology approaches in vivo and in vitro. We identify two critical elements in the Tail domain of Pkl1 that mediate γ-TuSC binding and trigger release of γ-tubulin from γ-TuRC. Such action disrupts the MTOC and results in failed mitotic spindle assembly. This study is the first demonstration that a motor protein directly affects the structural composition of the γ-TuRC, and we provide details of this mechanism that may be of broad biological importance.
    MeSH term(s) Amino Acid Sequence ; Kinesin/chemistry ; Kinesin/metabolism ; Models, Biological ; Molecular Sequence Data ; Multiprotein Complexes/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Schizosaccharomyces/cytology ; Schizosaccharomyces/metabolism ; Schizosaccharomyces pombe Proteins/chemistry ; Schizosaccharomyces pombe Proteins/metabolism ; Spindle Apparatus/metabolism ; Structure-Activity Relationship ; Tubulin/metabolism
    Chemical Substances Multiprotein Complexes ; PKL1 protein, S pombe ; Schizosaccharomyces pombe Proteins ; Tubulin ; Kinesin (EC 3.6.4.4)
    Language English
    Publishing date 2013-02-06
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2146183-1
    ISSN 1551-4005 ; 1538-4101 ; 1554-8627
    ISSN (online) 1551-4005
    ISSN 1538-4101 ; 1554-8627
    DOI 10.4161/cc.23822
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    Zs.A 5881: Show issues Location:
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  5. Article ; Online: Functional replacement of fission yeast γ-tubulin small complex proteins Alp4 and Alp6 by human GCP2 and GCP3.

    Riehlman, Timothy D / Olmsted, Zachary T / Branca, Carmen N / Winnie, Adam M / Seo, Lan / Cruz, Leilani O / Paluh, Janet L

    Journal of cell science

    2013  Volume 126, Issue Pt 19, Page(s) 4406–4413

    Abstract: Microtubule-organizing centers such as the γ-tubulin ring complex (γ-TuRC) act as a template for polarized growth and regulation of microtubules that are essential for diverse cellular structures and processes in eukaryotes. New structural models of the ... ...

    Abstract Microtubule-organizing centers such as the γ-tubulin ring complex (γ-TuRC) act as a template for polarized growth and regulation of microtubules that are essential for diverse cellular structures and processes in eukaryotes. New structural models of the budding yeast γ-tubulin small complex (γ-TuSC) of the γ-TuRC combined with functional studies done in multiple eukaryotes are revealing the first mechanistic clues into control of microtubule nucleation and organization. Cross-species studies of human and budding yeast γ-TuSC proteins in fission yeast revealed conserved and divergent structural and functional features of the γ-TuSC. We show genetically that GCP3/Spc98 function is fully conserved with Alp6 across species but that functional differences exist between GCP2/Spc97 and Alp4. By further analysis of human γ-TuSC proteins, we found that GCP3 assembles normally into the >2000 kDa fission yeast γ-TuRC and that the GCP3 gene replaces fission yeast alp6. Interestingly, human GCP2 replaces the essential alp4 gene but is unable to rescue a normally recessive G1 defect of the alp4-1891 allele that results in loss of γ-TuRC from poles in subsequent cell cycles. Biochemically, GCP2 incorporation into fission yeast γ-TuRC is limited in the presence of Alp4; instead, the bulk of GCP2 fractionates as smaller complexes. By generating a functional Alp4-GCP2 chimeric protein we determined that the GCP2 N-terminal domain limits its ability to fully displace or compete with Alp4 during γ-TuRC assembly. Our findings have broad importance for understanding the essential domains of γ-TuSC proteins in the γ-TuRC mechanism.
    MeSH term(s) Amino Acid Sequence ; Humans ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Models, Molecular ; Molecular Sequence Data ; Protein Structure, Secondary ; Schizosaccharomyces/genetics ; Schizosaccharomyces/metabolism ; Schizosaccharomyces pombe Proteins/genetics ; Schizosaccharomyces pombe Proteins/metabolism ; Tubulin/chemistry ; Tubulin/genetics ; Tubulin/metabolism
    Chemical Substances Alp4 protein, S pombe ; Alp6 protein, S pombe ; Microtubule-Associated Proteins ; Schizosaccharomyces pombe Proteins ; TUBGCP2 protein, human ; TUBGCP3 protein, human ; Tubulin
    Language English
    Publishing date 2013-10-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2993-2
    ISSN 1477-9137 ; 0021-9533
    ISSN (online) 1477-9137
    ISSN 0021-9533
    DOI 10.1242/jcs.128173
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  6. Article ; Online: miR-23∼27∼24 clusters control effector T cell differentiation and function.

    Cho, Sunglim / Wu, Cheng-Jang / Yasuda, Tomoharu / Cruz, Leilani O / Khan, Aly Azeem / Lin, Ling-Li / Nguyen, Duc T / Miller, Marina / Lee, Hyang-Mi / Kuo, Ming-Ling / Broide, David H / Rajewsky, Klaus / Rudensky, Alexander Y / Lu, Li-Fan

    The Journal of experimental medicine

    2016  Volume 213, Issue 2, Page(s) 235–249

    Abstract: Coordinated repression of gene expression by evolutionarily conserved microRNA (miRNA) clusters and paralogs ensures that miRNAs efficiently exert their biological impact. Combining both loss- and gain-of-function genetic approaches, we show that the miR- ...

    Abstract Coordinated repression of gene expression by evolutionarily conserved microRNA (miRNA) clusters and paralogs ensures that miRNAs efficiently exert their biological impact. Combining both loss- and gain-of-function genetic approaches, we show that the miR-23∼27∼24 clusters regulate multiple aspects of T cell biology, particularly helper T (Th) 2 immunity. Low expression of this miRNA family confers proper effector T cell function at both physiological and pathological settings. Further studies in T cells with exaggerated regulation by individual members of the miR-23∼27∼24 clusters revealed that miR-24 and miR-27 collaboratively limit Th2 responses through targeting IL-4 and GATA3 in both direct and indirect manners. Intriguingly, although overexpression of the entire miR-23 cluster also negatively impacts other Th lineages, enforced expression of miR-24, in contrast to miR-23 and miR-27, actually promotes the differentiation of Th1, Th17, and induced regulatory T cells, implying that under certain conditions, miRNA families can fine tune the biological effects of their regulation by having individual members antagonize rather than cooperate with each other. Together, our results identify a miRNA family with important immunological roles and suggest that tight regulation of miR-23∼27∼24 clusters in T cells is required to maintain optimal effector function and to prevent aberrant immune responses.
    MeSH term(s) Animals ; Asthma/genetics ; Asthma/immunology ; Asthma/pathology ; Cell Differentiation/genetics ; Cell Differentiation/immunology ; Disease Models, Animal ; GATA3 Transcription Factor/biosynthesis ; GATA3 Transcription Factor/genetics ; Gene Expression Regulation ; Gene Regulatory Networks ; Interleukin-4/biosynthesis ; Interleukin-4/genetics ; Lymphocyte Activation/genetics ; Mice ; Mice, Transgenic ; MicroRNAs/genetics ; MicroRNAs/immunology ; Multigene Family ; Phenotype ; T-Lymphocyte Subsets/cytology ; T-Lymphocyte Subsets/immunology ; T-Lymphocytes, Helper-Inducer/cytology ; T-Lymphocytes, Helper-Inducer/immunology ; Th2 Cells/cytology ; Th2 Cells/immunology
    Chemical Substances GATA3 Transcription Factor ; Gata3 protein, mouse ; MicroRNAs ; Mirn23b microRNA, mouse ; Mirn24 microRNA, mouse ; Mirn27 microRNA, mouse ; Interleukin-4 (207137-56-2)
    Language English
    Publishing date 2016-02-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20150990
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