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  • 1
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    Differential effects of c-Src and c-Yes on the endocytic vesicle-mediated trafficking events at the Sertoli cell blood-testis barrier: an in vitro study
    American Physiological Society ; 2014
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 307, No. 7 ( 2014-10-01), p. E553-E562
    Details
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 307, No. 7 ( 2014-10-01), p. E553-E562
    Abstract: The blood-testis barrier (BTB) is one of the tightest blood-tissue barriers in the mammalian body. However, it undergoes cyclic restructuring during the epithelial cycle of spermatogenesis in which the “old” BTB located above the preleptotene spermatocytes being transported across the immunological barrier is “disassembled,” whereas the “new” BTB found behind these germ cells is rapidly “reassembled,” i.e., mediated by endocytic vesicle-mediated protein trafficking events. Thus, the immunological barrier is maintained when preleptotene spermatocytes connected in clones via intercellular bridges are transported across the BTB. Yet the underlying mechanism(s) in particular the involving regulatory molecules that coordinate these events remains unknown. We hypothesized that c-Src and c-Yes might work in contrasting roles in endocytic vesicle-mediated trafficking, serving as molecular switches, to effectively disassemble and reassemble the old and the new BTB, respectively, to facilitate preleptotene spermatocyte transport across the BTB. Following siRNA-mediated specific knockdown of c-Src or c-Yes in Sertoli cells, we utilized biochemical assays to assess the changes in protein endocytosis, recycling, degradation and phagocytosis. c-Yes was found to promote endocytosed integral membrane BTB proteins to the pathway of transcytosis and recycling so that internalized proteins could be effectively used to assemble new BTB from the disassembling old BTB, whereas c-Src promotes endocytosed Sertoli cell BTB proteins to endosome-mediated protein degradation for the degeneration of the old BTB. By using fluorescence beads mimicking apoptotic germ cells, Sertoli cells were found to engulf beads via c-Src-mediated phagocytosis. A hypothetical model that serves as the framework for future investigation is thus proposed.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    URL: Article
    DOI: 10.1152/ajpendo.00176.2014
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2014
    detail.hit.zdb_id: 1477331-4
    SSG: 12
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  • 2
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    14-3-3 Protein Regulates Cell Adhesion in the Seminiferous Epithelium of Rat Testes
    The Endocrine Society ; 2009
    In:  Endocrinology Vol. 150, No. 10 ( 2009-10-01), p. 4713-4723
    Details
    In: Endocrinology, The Endocrine Society, Vol. 150, No. 10 ( 2009-10-01), p. 4713-4723
    Abstract: Polarity proteins have been implicated in regulating and maintaining tight junction (TJ) and cell polarity in epithelia. Here we report 14-3-3θ, the homolog of Caenorhabditis elegans Par5 in mammalian cells, which is known to confer cell polarity at TJ, is found at the apical ectoplasmic specialization (ES), a testis-specific adherens junction type restricted to the Sertoli cell-elongating spermatid interface, in which TJ is absent. 14-3-3θ was shown to play a critical role in conferring cell adhesion at the apical ES. A loss of 14-3-3θ expression at the apical ES was detected in the seminiferous epithelium before spermiation. Involvement of 14-3-3θ in Sertoli cell adhesion was confirmed by its knockdown by RNA interference in Sertoli cells cultured in vitro with established TJ permeability barrier that mimicked the blood-testis barrier (BTB) in vivo. Mislocalization of N-cadherin and zonula occludens-1, but not α- and β-catenins, was observed after 14-3-3θ knockdown in Sertoli cells, moving from the cell-cell interface to cytosol, indicating a disruption of cell adhesion. Studies by endocytosis assay illustrated that this loss of cell adhesion was mediated by an increase in the kinetics of endocytosis of N-cadherin and junctional adhesion molecule-A at the BTB, which may represent a general mechanism by which polarity proteins regulate cell adhesion. In summary, the testis is using 14-3-3θ to regulate cell adhesion at the apical ES to facilitate spermiation and at the BTB to facilitate the transit of preleptotene spermatocytes at stages VIII–IX of the epithelial cycle. 14-3-3θ may act as a molecular switch that coordinates these two cellular events in the seminiferous epithelium during spermatogenesis.
    Type of Medium: Online Resource
    ISSN: 0013-7227 , 1945-7170
    URL: Article
    DOI: 10.1210/en.2009-0427
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2009
    detail.hit.zdb_id: 2011695-0
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  • 3
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    Online Resource
    14-3-3 and its binding partners are regulators of protein–protein interactions during spermatogenesis
    Bioscientifica ; 2009
    In:  Journal of Endocrinology Vol. 202, No. 3 ( 2009-04-14), p. 327-336
    Details
    In: Journal of Endocrinology, Bioscientifica, Vol. 202, No. 3 ( 2009-04-14), p. 327-336
    Abstract: During spermatogenesis, spermiation takes place at the adluminal edge of the seminiferous epithelium at stage VIII of the epithelial cycle during which fully developed spermatids (i.e. spermatozoa) detach from the epithelium in adult rat testes. This event coincides with the migration of preleptotene/leptotene spermatocytes across the blood–testis barrier from the basal to the apical (or adluminal) compartment. At stage XIV of the epithelial cycle, Pachytene spermatocytes (diploid, 2n) differentiate into diplotene spermatocytes (tetraploid, 4n) in the apical compartment of the epithelium, which begin meiosis I to be followed by meiosis II to form spermatids (haploid, 1n) at stage XIV of the epithelial cycle. These spermatids, in turn, undergo extensive morphological changes and traverse the seminiferous epithelium until they differentiate into elongated spermatids. Thus, there are extensive changes at the Sertoli–Sertoli and Sertoli–germ cell interface via protein ‘coupling’ and ‘uncoupling’ between cell adhesion protein complexes, as well as changes in interactions between integral membrane proteins and their peripheral adaptors, regulatory protein kinases and phosphatases, and the cytoskeletal proteins. These precisely coordinated protein–protein interactions affect cell adhesion and cell movement. In this review, we focus on the 14-3-3 protein family, whose members have different binding partners in the seminiferous epithelium. Recent studies have illustrated that 14-3-3 affects protein–protein interactions in the seminiferous epithelium, and regulates cell adhesion possibly via its effects on intracellular protein trafficking and cell-polarity proteins. This review provides a summary on the latest findings regarding the role of 14-3-3 family of proteins and their potential implications on spermatogenesis. We also highlight research areas that deserve attentions by investigators.
    Type of Medium: Online Resource
    ISSN: 0022-0795 , 1479-6805
    URL: Article
    DOI: 10.1677/JOE-09-0041
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2009
    detail.hit.zdb_id: 1474892-7
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  • 4
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    Abstract 6164: Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert tumor microenvironment
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6164-6164
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 6164-6164
    Abstract: Immune checkpoint blockade (ICB) has demonstrated clinical success in “inflamed” tumors with significant T-cell infiltrates, but tumors with an immune-desert tumor microenvironment (TME) fail to benefit. The tumor cell-intrinsic molecular mechanisms of the immune-desert phenotype remain poorly understood. Here, we demonstrate that inactivation of the Polycomb-repressive complex 2 (PRC2) core components, EED or SUZ12, a prevalent genetic event in malignant peripheral nerve sheath tumor (MPNST) and sporadically in other cancer types, drives a context-dependent immune-desert TME. PRC2 inactivation reprograms the chromatin landscape that leads to a cell-autonomous shift from primed baseline signaling-dependent cellular responses (e.g., interferon γ) to PRC2-regulated development and cellular differentiation transcriptional programs. Further, PRC2 inactivation reprograms the TME, leads to diminished tumor immune infiltrates and immune evasion through reduced chemokine production and impaired antigen presentation and T-cell priming, and confers ICB primary resistance through blunted T-cell recruitment in vivo. We demonstrate that strategies that enhancing innate immunity via intratumoral delivery of inactivated modified vaccinia virus Ankara (MVA) leads to increased tumor immune infiltrates and sensitizes PRC2-loss tumors to ICB. Our results provide novel molecular mechanisms of context-dependent dysfunctional epigenetic reprogramming that underline the immune-desert phenotype in MPNST and other cancers with PRC2 inactivation. Importantly, our findings highlight genetic-inactivation of PRC2 as a novel context-dependent ICB therapeutic resistance biomarker in cancer, and caution that therapeutic strategies that non-selectively target PRC2 in the host may lead to undesirable context-dependent immune evasion and ICB resistance in tumors. Our studies also point to intratumoral delivery of immunogenic therapeutic viruses as an initial strategy to modulate the immune-desert TME and capitalize on the clinical benefit of ICB. Citation Format: Juan Yan, Yuedan Chen, Amish J. Patel, Cindy J. Lee, Sarah Warda, Briana G. Nixon, Elissa W. P. Wong, Miguel A. Miranda-Román, Ning Yang, Yi Wang, Jessica Sher, Emily Giff, Fanying Tang, Ekta Khurana, Sam Singer, Yang Liu, Phillip M. Galbo, Jesper L. Maag, Richard P. Koche, Deyou Zheng, Cristina R. Antonescu, Ming Li, Liang Deng, Yu Chen, Ping Chi. Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6164.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-6164
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
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    Online Resource
    Palladin Is a Regulator of Actin Filament Bundles at the Ectoplasmic Specialization in Adult Rat Testes
    The Endocrine Society ; 2013
    In:  Endocrinology Vol. 154, No. 5 ( 2013-05-01), p. 1907-1920
    Details
    In: Endocrinology, The Endocrine Society, Vol. 154, No. 5 ( 2013-05-01), p. 1907-1920
    Abstract: In rat testes, the ectoplasmic specialization (ES) at the Sertoli-Sertoli and Sertoli-spermatid interface known as the basal ES at the blood-testis barrier and the apical ES in the adluminal compartment, respectively, is a testis-specific adherens junction. The remarkable ultrastructural feature of the ES is the actin filament bundles that sandwiched in between the cisternae of endoplasmic reticulum and apposing plasma membranes. Although these actin filament bundles undergo extensive reorganization to switch between their bundled and debundled state to facilitate blood-testis barrier restructuring and spermatid adhesion/transport, the regulatory molecules underlying these events remain unknown. Herein we report findings of an actin filament cross-linking/bundling protein palladin, which displayed restrictive spatiotemporal expression at the apical and the basal ES during the epithelial cycle. Palladin structurally interacted and colocalized with Eps8 (epidermal growth factor receptor pathway substrate 8, an actin barbed end capping and bundling protein) and Arp3 (actin related protein 3, which together with Arp2 form the Arp2/3 complex to induce branched actin nucleation, converting bundled actin filaments to an unbundled/branched network), illustrating its role in regulating actin filament bundle dynamics at the ES. A knockdown of palladin in Sertoli cells in vitro with an established tight junction (TJ)-permeability barrier was found to disrupt the TJ function, which was associated with a disorganization of actin filaments that affected protein distribution at the TJ. Its knockdown in vivo also perturbed F-actin organization that led to a loss of spermatid polarity and adhesion, causing defects in spermatid transport and spermiation. In summary, palladin is an actin filament regulator at the ES.
    Type of Medium: Online Resource
    ISSN: 0013-7227 , 1945-7170
    URL: Article
    DOI: 10.1210/en.2012-2269
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2013
    detail.hit.zdb_id: 2011695-0
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  • 6
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    ETV4 mediates dosage-dependent prostate tumor initiation and cooperates with p53 loss to generate prostate cancer
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Advances Vol. 9, No. 14 ( 2023-04-05)
    Details
    In: Science Advances, American Association for the Advancement of Science (AAAS), Vol. 9, No. 14 ( 2023-04-05)
    Abstract: Sufficient protein dosage of ETV4 can directly transform prostate epithelial cells, which recapitulates early human disease.
    Type of Medium: Online Resource
    ISSN: 2375-2548
    URL: Article
    DOI: 10.1126/sciadv.adc9446
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
    detail.hit.zdb_id: 2810933-8
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  • 7
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    Focal adhesion kinase is a blood–testis barrier regulator
    Proceedings of the National Academy of Sciences ; 2009
    In:  Proceedings of the National Academy of Sciences Vol. 106, No. 23 ( 2009-06-09), p. 9298-9303
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 106, No. 23 ( 2009-06-09), p. 9298-9303
    Abstract: In mammalian testes, such as rats, the mechanism(s) that regulate blood–testis barrier (BTB) restructuring at stages VIII–IX of the seminiferous epithelial cycle of spermatogenesis to facilitate the transit of preleptotene/leptotene spermatocytes is not known. This is due to the lack of information on the regulatory proteins at the BTB. Herein, focal adhesion kinase (FAK), a nonreceptor protein tyrosine kinase, is shown to structurally interact with occludin and ZO-1 to form a functional protein complex at the BTB. Its expression at the BTB in the seminiferous epithelium is stage specific, being lowest at stage VIII–IX tubules, analogous to the expression pattern of occludin. Using primary Sertoli cells cultured in vitro with an established tight junction (TJ) permeability barrier that mimics the BTB in vivo, the knockdown of FAK by RNAi led to a transient disruption of the TJ barrier. This was accompanied by a loss of association between occludin and ZO-1, likely the result of reduced occludin phosphorylation at Tyr and Ser residues, but not Thr, which in turn led to a redistribution of occludin at the Sertoli–Sertoli cell interface, moving from cell membrane into cell cytosol, thereby disrupting the BTB. These findings suggest that a similar mechanism is in place in the testis in vivo to regulate BTB restructuring to facilitate the transit of primary spermatocytes. Furthermore, FAK was shown to be a molecular target of cadmium because its knockdown would desensitize Sertoli cells to cadmium-induced TJ barrier disruption. In summary, FAK is a unique regulator of BTB dynamics in the testis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0813113106
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2009
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 8
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    Online Resource
    Par3/Par6 polarity complex coordinates apical ectoplasmic specialization and blood–testis barrier restructuring during spermatogenesis
    Proceedings of the National Academy of Sciences ; 2008
    In:  Proceedings of the National Academy of Sciences Vol. 105, No. 28 ( 2008-07-15), p. 9657-9662
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 28 ( 2008-07-15), p. 9657-9662
    Abstract: The Par3/Par6/aPKC and the CRB3/Pals1/PATJ polarity complexes are involved in regulating apical ectoplasmic specialization (ES) and blood–testis barrier (BTB) restructuring in the testis. Par6 was a component of the apical ES and the BTB. However, its level was considerably diminished at both sites at stage VIII of the cycle. Par6 also formed a stable complex with Pals1 and JAM-C (a component of the apical ES) in normal testes. When rats were treated with adjudin to induce apical ES restructuring without compromising the BTB, Par6 staining virtually disappeared at the apical ES in misaligned spermatids before their depletion. Additionally, the Par6/Pals1 complex became tightly associated with Src kinase, rendering a loss of association of the Par6/Pals1 complex with JAM-C, thereby destabilizing apical ES to facilitate spermatid loss. Primary Sertoli cell cultures with established functional BTB, but without apical ES, were next used to assess the Par6-based complex on BTB dynamics. When either Par6 or Par3 was knocked down by RNAi in Sertoli cell epithelium, a significant loss of the corresponding protein by ≈60% in cells vs. controls was detected, alongside with a decline in aPKC after Par6, but not Par3, knockdown. This Par3 or Par6 knockdown also led to a transient loss of selected BTB proteins at the cell–cell interface, thereby compromising the BTB integrity. These findings illustrate that the Par6/Par3-based polarity complex likely coordinates the events of apical ES and BTB restructuring that take place concurrently at the opposing ends of adjacent Sertoli cells in the seminiferous epithelium during spermatogenesis.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0801527105
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2008
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 9
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    Online Resource
    Alternative transcription initiation leads to expression of a novel ALK isoform in cancer
    Springer Science and Business Media LLC ; 2015
    In:  Nature Vol. 526, No. 7573 ( 2015-10), p. 453-457
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 526, No. 7573 ( 2015-10), p. 453-457
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/nature15258
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2015
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 10
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    Online Resource
    An Occludin-Focal Adhesion Kinase Protein Complex at the Blood-Testis Barrier: A Study Using the Cadmium Model
    The Endocrine Society ; 2009
    In:  Endocrinology Vol. 150, No. 7 ( 2009-07-01), p. 3336-3344
    Details
    In: Endocrinology, The Endocrine Society, Vol. 150, No. 7 ( 2009-07-01), p. 3336-3344
    Abstract: Several integral membrane proteins that constitute the blood-testis barrier (BTB) in mammalian testes, in particular rodents, are known to date. These include tight junction (TJ) proteins (e.g. occludin, junctional adhesion molecule-A, claudins), basal ectoplasmic specialization proteins (e.g. N-cadherin), and gap junction proteins (e.g. connexin43). However, the regulators (e.g. protein kinases and phosphatases) that affect these proteins, such as their interaction with the cytoskeletal actin, which in turn confer cell adhesion at the TJ, remain largely unknown. We report herein that focal adhesion kinase (FAK) is a putative interacting partner of occludin, but not claudin-11 or junctional adhesion molecule-A. Immunohistochemistry and fluorescence microscopy studies illustrated that the expression of FAK in the seminiferous epithelium of adult rat testes was stage specific. FAK colocalized with occludin at the BTB in virtually all stages of the seminiferous epithelial cycle but considerably diminished in stages VIII–IX, at the time of BTB restructuring to facilitate the transit of primary leptotene spermatocytes. Using Sertoli cells cultured in vitro with established TJ-permeability barrier and ultrastructures of TJ, basal ectoplasmic specialization and desmosome-like junction that mimicked the BTB in vivo, FAK was shown to colocalize with occludin and zonula occludens-1 (ZO-1) at the Sertoli-Sertoli cell interface. When these Sertoli cell cultures were treated with CdCl2 to perturb the TJ-barrier function, occludin underwent endocytic-mediated internalization in parallel with FAK and ZO-1. Thus, these findings demonstrate that FAK is an integrated regulatory component of the occludin-ZO-1 protein complex, suggesting that functional studies can be performed to study the role of FAK in BTB dynamics.
    Type of Medium: Online Resource
    ISSN: 0013-7227 , 1945-7170
    URL: Article
    DOI: 10.1210/en.2008-1741
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2009
    detail.hit.zdb_id: 2011695-0
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