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Literatura científica selecionada sobre o tema "Kpnb1"

Autor: Grafiati

Publicado: 29 de março de 2025

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Artigos de revistas sobre o assunto "Kpnb1"

Mihalas, Bettina P., Patrick S. Western, Kate L. Loveland, Eileen A. McLaughlin e Janet E. Holt. "Changing expression and subcellular distribution of karyopherins during murine oogenesis". REPRODUCTION 150, n.º 6 (dezembro de 2015): 485–96. http://dx.doi.org/10.1530/rep-14-0585.

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Mammalian oocyte growth and development is driven by a strict program of gene expression that relies on the timely presence of transcriptional regulators via nuclear pores. By targeting specific cargos for nucleo-cytoplasmic transport, karyopherin (KPN) proteins are key to the relocation of essential transcription factors and chromatin-remodelling factors into and out of the nucleus. Using multiple complementary techniques, here we establish that KPNA genes and proteins are dynamically expressed and relocalised throughout mouse oogenesis and folliculogenesis. Of the KPNAs examined (Kpna1, Kpna2, Kpna3, Kpna4, Kpna6, Kpna7, Kpnb1, Ipo5 and Xpo1), all were expressed in the embryonic ovary with up-regulation of protein levels concomitant with meiotic entry for KPNA2, accompanied by the redistribution of the cellular localisation of KPNA2 and XPO1. In contrast, postnatal folliculogenesis revealed significant up-regulation of Kpna1, Kpna2, Kpna4, Kpna6 and Ipo5 and down-regulation of Kpnb1, Kpna7 and Xpo1 at the primordial to primary follicle transition. KPNAs exhibited different localisation patterns in both oocytes and granulosa cells during folliculogenesis, with three KPNAs – KPNA1, KPNA2 and IPO5 – displaying marked enrichment in the nucleus by antral follicle stage. Remarkably, varied subcellular expression profiles were also identified in isolated pre-ovulatory oocytes with KPNAs KPNA2, KPNB1 and IPO5 detected in the cytoplasm and at the nuclear rim and XPO1 in cytoplasmic aggregates. Intriguingly, meiotic spindle staining was also observed for KPNB1 and XPO1 in meiosis II eggs, implying roles for KPNAs outside of nucleo-cytoplasmic transport. Thus, we propose that KPNAs, by targeting specific cargoes, are likely to be key regulators of oocyte development.

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Sato, Kota, Hironori Yoshino, Yoshiaki Sato, Manabu Nakano e Eichi Tsuruga. "ΔNp63 Regulates Radioresistance in Human Head and Neck Squamous Carcinoma Cells". Current Issues in Molecular Biology 45, n.º 8 (27 de julho de 2023): 6262–71. http://dx.doi.org/10.3390/cimb45080394.

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Radiation therapy is commonly used to treat head and neck squamous cell carcinoma (HNSCC); however, recurrence results from the development of radioresistant cancer cells. Therefore, it is necessary to identify the underlying mechanisms of radioresistance in HNSCC. Previously, we showed that the inhibition of karyopherin-β1 (KPNB1), a factor in the nuclear transport system, enhances radiation-induced cytotoxicity, specifically in HNSCC cells, and decreases the localization of SCC-specific transcription factor ΔNp63. This suggests that ΔNp63 may be a KPNB1-carrying nucleoprotein that regulates radioresistance in HNSCC. Here, we determined whether ΔNp63 is involved in the radioresistance of HNSCC cells. Cell survival was measured by a colony formation assay. Apoptosis was assessed by annexin V staining and cleaved caspase-3 expression. The results indicate that ΔNp63 knockdown decreased the survival of irradiated HNSCC cells, increased radiation-induced annexin V+ cells, and cleaved caspase-3 expression. These results show that ΔNp63 is involved in the radioresistance of HNSCC cells. We further investigated which specific karyopherin-α (KPNA) molecules, partners of KPNB1 for nuclear transport, are involved in nuclear ΔNp63 expression. The analysis of nuclear ΔNp63 protein expression suggests that KPNA1 is involved in nuclear ΔNp63 expression. Taken together, our results suggest that ΔNp63 is a KPNB1-carrying nucleoprotein that regulates radioresistance in HNSCC.

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Hazawa, Masaharu, Hironori Yoshino, Yuta Nakagawa, Reina Shimizume, Keisuke Nitta, Yoshiaki Sato, Mariko Sato, Richard W. Wong e Ikuo Kashiwakura. "Karyopherin-β1 Regulates Radioresistance and Radiation-Increased Programmed Death-Ligand 1 Expression in Human Head and Neck Squamous Cell Carcinoma Cell Lines". Cancers 12, n.º 4 (8 de abril de 2020): 908. http://dx.doi.org/10.3390/cancers12040908.

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Nuclear transport receptors, such as karyopherin-β1 (KPNB1), play important roles in the nuclear-cytoplasmic transport of macromolecules. Recent evidence indicates the involvement of nuclear transport receptors in the progression of cancer, making these receptors promising targets for the treatment of cancer. Here, we investigated the anticancer effects of KPNB1 blockage or in combination with ionizing radiation on human head and neck squamous cell carcinoma (HNSCC). HNSCC cell line SAS and Ca9-22 cells were used in this study. Importazole, an inhibitor of KPNB1, or knockdown of KPNB1 by siRNA transfection were applied for the blockage of KPNB1 functions. The roles of KPNB1 on apoptosis induction and cell surface expression levels of programmed death-ligand 1 (PD-L1) in irradiated HNSCC cells were investigated. The major findings of this study are that (i) blockage of KPNB1 specifically enhanced the radiation-induced apoptosis and radiosensitivity of HNSCC cells; (ii) importazole elevated p53-upregulated modulator of apoptosis (PUMA) expression via blocking the nuclear import of SCC-specific oncogene ΔNp63 in HNSCC cells; and (iii) blockage of KPNB1 attenuated the upregulation of cell surface PD-L1 expression on irradiated HNSCC cells. Taken together, these results suggest that co-treatment with KPNB1 blockage and ionizing radiation is a promising strategy for the treatment of HNSCC.

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Kodama, Michiko, Takahiro Kodama, Justin Y. Newberg, Hiroyuki Katayama, Makoto Kobayashi, Samir M. Hanash, Kosuke Yoshihara et al. "In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer". Proceedings of the National Academy of Sciences 114, n.º 35 (15 de agosto de 2017): E7301—E7310. http://dx.doi.org/10.1073/pnas.1705441114.

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Epithelial ovarian cancer (EOC) is a deadly cancer, and its prognosis has not been changed significantly during several decades. To seek new therapeutic targets for EOC, we performed an in vivo dropout screen in human tumor xenografts using a pooled shRNA library targeting thousands of druggable genes. Then, in follow-up studies, we performed a second screen using a genome-wide CRISPR/Cas9 library. These screens identified 10 high-confidence drug targets that included well-known oncogenes such as ERBB2 and RAF1, and novel oncogenes, notably KPNB1, which we investigated further. Genetic and pharmacological inhibition showed that KPNB1 exerts its antitumor effects through multiphase cell cycle arrest and apoptosis induction. Mechanistically, proteomic studies revealed that KPNB1 acts as a master regulator of cell cycle-related proteins, including p21, p27, and APC/C. Clinically, EOC patients with higher expression levels of KPNB1 showed earlier recurrence and worse prognosis than those with lower expression levels of KPNB1. Interestingly, ivermectin, a Food and Drug Administration-approved antiparasitic drug, showed KPNB1-dependent antitumor effects on EOC, serving as an alternative therapeutic toward EOC patients through drug repositioning. Last, we found that the combination of ivermectin and paclitaxel produces a stronger antitumor effect on EOC both in vitro and in vivo than either drug alone. Our studies have thus identified a combinatorial therapy for EOC, in addition to a plethora of potential drug targets.

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Yoshino, Hironori, Yoshiaki Sato e Manabu Nakano. "KPNB1 Inhibitor Importazole Reduces Ionizing Radiation-Increased Cell Surface PD-L1 Expression by Modulating Expression and Nuclear Import of IRF1". Current Issues in Molecular Biology 43, n.º 1 (19 de maio de 2021): 153–62. http://dx.doi.org/10.3390/cimb43010013.

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Programmed death-ligand 1 (PD-L1) is an immune checkpoint molecule that negatively regulates anti-tumor immunity. Recent reports indicate that anti-cancer treatments, such as radiation therapy, increase PD-L1 expression on the surface of tumor cells. We previously reported that the nuclear transport receptor karyopherin-β1 (KPNB1) is involved in radiation-increased PD-L1 expression on head-and-neck squamous cell carcinoma cells. However, the mechanisms underlying KPNB1-mediated, radiation-increased PD-L1 expression remain unknown. Thus, the mechanisms of radiation-increased, KPNB1-mediated PD-L1 expression were investigated by focusing on the transcription factor interferon regulatory factor 1 (IRF1), which is reported to regulate PD-L1 expression. Western blot analysis showed that radiation increased IRF1 expression. In addition, flow cytometry showed that IRF1 knockdown decreased cell surface PD-L1 expression of irradiated cells but had a limited effect on non-irradiated cells. These findings suggest that the upregulation of IRF1 after irradiation is required for radiation-increased PD-L1 expression. Notably, immunofluorescence and western blot analyses revealed that KPNB1 inhibitor importazole not only diffused nuclear localization of IRF1 but also decreased IRF1 upregulation by irradiation, which attenuated radiation-increased PD-L1 expression. Taken together, these findings suggest that KPNB1 mediates radiation-increased cell surface PD-L1 expression through both upregulation and nuclear import of IRF1.

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Park, Chanhee, Jiwon Oh, Won Mo Lee, Hye Ran Koh, Uy Dong Sohn, Seung Wook Ham e Kyungsoo Oh. "Inhibition of NUPR1–Karyopherin β1 Binding Increases Anticancer Drug Sensitivity". International Journal of Molecular Sciences 22, n.º 6 (10 de março de 2021): 2794. http://dx.doi.org/10.3390/ijms22062794.

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Background: Nuclear protein-1 (NUPR1, also known as p8/Com-1) is a transcription factor involved in the regulation of cellular stress responses, including serum starvation and drug stimulation. Methods: We investigated the mechanism of NUPR1 nuclear translocation involving karyopherin β1 (KPNB1), using a single-molecule binding assay and confocal microscopy. The cellular effects associated with NUPR1–KPNB1 inhibition were investigated by gene expression profiling and cell cycle analysis. Results: The single-molecule binding assay revealed that KPNB1 bound to NUPR1 with a binding affinity of 0.75 nM and that this binding was blocked by the aminothiazole ATZ-502. Following doxorubicin-only treatment, NUPR1 was translocated to the nucleus in more than 90% and NUPR1 translocation was blocked by the ATZ-502 combination treatment in MDA-MB-231 with no change in NUPR1 expression, providing strong evidence that NUPR1 nuclear translocation was directly inhibited by the ATZ-502 treatment. Inhibition of KPNB1 and NUPR1 binding was associated with a synergistic anticancer effect (up to 19.6-fold) in various cancer cell lines. NUPR1-related genes were also downregulated following the doxorubicin–ATZ-502 combination treatment. Conclusion: Our current findings clearly demonstrate that NUPR1 translocation into the nucleus requires karyopherin β1 binding. Inhibition of the KPNB1 and NUPR1 interaction may constitute a new cancer therapeutic approach that can increase the drug efficacy while reducing the side effects.

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Zeng, Yan, Yuna Wang, Zhiqin Wu, Kang Kang, Xiao Peng, Wenda Peng, Junle Qu, Lin Liu, J. Usha Raj e Deming Gou. "miR-9 enhances the transactivation of nuclear factor of activated T cells by targeting KPNB1 and DYRK1B". American Journal of Physiology-Cell Physiology 308, n.º 9 (1 de maio de 2015): C720—C728. http://dx.doi.org/10.1152/ajpcell.00299.2014.

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The fast response to stimuli and subsequent activation of the nuclear factor of activated T cells (NFAT) signaling pathway play an essential role in human T cell functions. MicroRNAs (miRNAs) are increasingly implicated in regulation of numerous biological and pathological processes. In this study we demonstrate a novel function of miRNA-9 (miR-9) in regulation of the NFAT signaling pathway. Upon PMA-ionomycin stimulation, miR-9 was markedly increased, consistent with NFAT activation. Overexpression of miR-9 significantly enhanced NFAT activity and accelerated NFAT dephosphorylation and its nuclear translocation in response to PMA-ionomycin. Karyopherin-β1 (KPNB1, a nucleocytoplasmic transporter) and dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B) were identified as direct targets of miR-9. Functionally, miR-9 promoted IL-2 production in stimulated human lymphocyte Jurkat T cells. Collectively, our data reveal a novel role for miR-9 in regulation of the NFAT pathway by targeting KPNB1 and DYRK1B.

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Kim, Yong-Hak, Siyoung Ha, Jungwon Kim e Seung Wook Ham. "Identification of KPNB1 as a Cellular Target of Aminothiazole Derivatives with Anticancer Activity". ChemMedChem 11, n.º 13 (31 de maio de 2016): 1406–9. http://dx.doi.org/10.1002/cmdc.201600159.

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Zeng, Renya, e Jixin Dong. "Abstract 5491: Targeting importin-YAP axis in pancreatic ductal adenocarcinoma". Cancer Research 82, n.º 12_Supplement (15 de junho de 2022): 5491. http://dx.doi.org/10.1158/1538-7445.am2022-5491.

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Abstract Background: To date, pancreatic ductal adenocarcinoma (PDAC) remains to have a dismal prognosis, with a 5-year survival rate of only 10%, which brings out an imperative to develop new therapeutic strategies to improve patient outcome. Recently, aberrant nucleocytoplasmic transport machinery in cancer cells has emerged as a rational therapeutic target. We aim to validate the nuclear importin complex involved in the import of macromolecules across the nuclear membrane as a potential therapeutic target in PDAC. Methods: Tet-inducible shRNA and FDA-approved agent (Ivermectin) were used for the inhibition of importins. Cell death (apoptosis and pyroptosis) was detected by western blot. In vivo tumor growth of human and mouse PDAC cells was evaluated in immunocompetent and immunodeficient animal models. MTT assay was employed to evaluate the patient-derived organoid viability following drug treatment. Results: We found that PDAC cells/patients harbored unusually higher levels of importins. Inducible knockdown of importin-α2/α5 (KPNA2/KPNA1) or importin-β1 (KPNB1) strongly suppressed PDAC tumor growth and induced apoptosis and pyroptosis. Interestingly, the importin inhibitor Ivermectin (an FDA-approved antiparasitic agent) worked effectively in PDAC cells, patient-derived organoids and animal models. Mechanistically, we show that importins associate with YAP (the transcriptional coactivator of the Hippo pathway) and control its expression at mRNA levels. In line with these observations, the expression levels of importin-αs, importin-β1, and YAP are positively correlated in PDAC patients. Conclusion: Our study identifies the importin complex as a prognostic marker and therapeutic target for pancreatic cancer and is expected to provide preclinical evidence for the evaluation of Ivermectin in PDAC patients. Citation Format: Renya Zeng, Jixin Dong. Targeting importin-YAP axis in pancreatic ductal adenocarcinoma [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 5491.

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Zhu, Zhi-Chuan, Ji-Wei Liu, Kui Li, Jing Zheng e Zhi-Qi Xiong. "KPNB1 inhibition disrupts proteostasis and triggers unfolded protein response-mediated apoptosis in glioblastoma cells". Oncogene 37, n.º 22 (9 de março de 2018): 2936–52. http://dx.doi.org/10.1038/s41388-018-0180-9.

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Mais fontes

Teses / dissertações sobre o assunto "Kpnb1"

Stelma, Tamara. "The effect of inhibiting KPNB1-mediated nuclear import on cancer cell biology and inflammatory transcription factor signalling". Doctoral thesis, University of Cape Town, 2018. http://hdl.handle.net/11427/27888.

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Cancer remains one of the major causes of morbidity and mortality globally. Many novel and innovative approaches have been employed to develop new chemotherapeutic strategies, of which targeted therapies aim to identify a molecular lesion or dysregulated pathway that cancer cells are dependent on. Research in our laboratory and others identified the nuclear import protein, Karyopherin β1 (KPNB1), to be overexpressed in various cancers and that inhibiting its expression blocks the proliferation of cancer cells. However, little is known about the potential role of KPNB1 in other cancer cell phenotypes and inflammatory signalling pathways. The aim of this study was to investigate the anticancer and anti-inflammatory effects of inhibiting nuclear import via KPNB1 and to characterise the in vivo effect of the small molecule inhibitor of nuclear import, INI-43, on tumour formation. Using siRNA and a small molecule inhibitor, INI-43, to inhibit KPNB1 we found that cervical cancer cell migration and invasion was significantly reduced. The reduced motility of cancer cells was associated with a decrease in MMP-2 and -9 expression and an increase in TIMP-1 and -2 expression following INI-43 treatment. This corresponded with a decrease in MMP-9 gelatinase activity in KPNB1-inhibited cervical cancer cells. Extended periods of KPNB1 inhibition lead to decreased proliferation and apoptosis. These changes in cancer cell biology when KPNB1 is inhibited may in part be due to its function as a nuclear transporter of transcription factors associated with cancer cell proliferation, migration and invasion. We therefore investigated the effects of KPNB1 inhibition on the nuclear localisation and transcriptional activity of key transcription factors; NFkB and AP-1, both having been implicated in many of the hallmarks of cancer. Immunofluorescent analysis and nuclear/cytoplasmic fractionation assays showed that KPNB1 inhibition blocked the nuclear localisation of NFkB. Electromobility shift assays confirmed a reduced NFkB binding to an NFkB DNA-binding sequence in the nuclear extract of KPNB1-inhibited cells. Luciferase reporter assays containing NFkB and/or AP-1 consensus binding sites showed reduced transcriptional activity for both transcription factors following KPNB1 inhibition. Associated with these changes in NFkB and AP-1 activity was reduced inflammatory cytokines; IL-6, IL-1β, TNF-α and GM-CSF target gene expression. To further characterise the role of INI-43 as a potential chemotherapeutic, the effects on tumour growth and development were investigated in an ectopic xenograft mouse model. INI-43 treatment significantly reduced tumour growth in mice and associated with the redistribution and reduction in KPNB1 levels. INI-43 treated tumours also showed altered morphological features including; better tissue differentiation and reduced inflammatory stromal infiltration, as well as reduced Ki-67 expression. The expression of extracellular matrix components and the cytoskeletal structure of cancer cells was analysed to further investigate the role of KPNB1 inhibition in tumour development. Inhibition of KPNB1 in cancer cells caused reduced expression of both collagen type IV and MMP-9. The redistribution of B-catenin and F-actin suggested that INI-43 treatment caused a loss of mesenchymal features required for tumour progression. The nuclear transport system has been of particular interest in recent years for the development of targeted anticancer drugs. However, most studies have focused on nuclear export inhibitors with little known on the potential of nuclear import inhibitors as anticancer drugs. This study provides evidence that inhibiting the nuclear import protein, KPNB1, has anti-inflammatory and anticancer effects and shows promise as an anticancer approach requiring further investigation.

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Queron, Brenda. "Étude du mode d'action du DV188 dans l'inhibition des propriétés souches et tumorigéniques des cellules souches cancéreuses de gliome". Electronic Thesis or Diss., Université Côte d'Azur, 2024. http://www.theses.fr/2024COAZ6050.

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Les glioblastomes se classent parmi les tumeurs cérébrales les plus agressives, caractérisées par une hétérogénéité intratumorale, une faible espérance de vie et une résistance prononcée aux traitements par radio-chimiothérapie. La complexité de ces tumeurs réside notamment dans la présence de cellules souches de gliomes (CSG), impliquées dans la prolifération clonale, l'invasivité et la récidive tumorale. Les CSG expriment divers marqueurs de cellules souches et de pluripotence tels que NANOG et SOX2. Ces facteurs de transcription doivent être transloqués dans le noyau cellulaire pour activer desprogrammes géniques qui maintiennent les propriétés souches et la tumorigénicité des CSG. Le traitement conventionnel consiste en une chirurgie, lorsque cela est possible, suivie d'une radiochimiothérapie. Malheureusement, ce traitement demeure limité, et les tumeurs récidivent en raison dela sélection et de la persistance des CSG résistantes après l'arrêt du traitement. Pour surmonter ce phénomène dû à la pression cytotoxique, nous avons cherché à élaborer une nouvelle stratégie thérapeutique visant à induire la différentiation des CSG en un phénotype moins agressif et plus sensible au traitement conventionnel. Dans ce contexte, nous avons identifié un composé chimique, le DV188, issu d'une bibliothèque de molécules synthétisée par l'Institut de Chimie de Nice. Nos résultats ont montré que ce composé est capable d'induire la différentiation des CSG dérivées de patients, d’inhiberleur capacité de prolifération clonale et de les sensibiliser à l’agent chimiothérapeutique de référence, le temozolomide (TMZ). Plus important encore, le DV188 empêche in vivo l'initiation et la progression tumorale sans affecter la survie de la souris après des mois de traitement. De plus, la combinaison de traitement du DV188 et du TMZ a démontré une efficacité deux fois supérieure à celle du TMZ seul. Au niveau moléculaire, nous avons mis en évidence un effet du DV188 sur le transport nucléaire de facteurs essentiels au maintien de l'état souche, perturbant ainsi les mécanismes favorisant l'agressivité et la tumorigénicité des CSG. Ces données soutiennent fortement l'idée que le ciblage de la différentiation des CSG représente une voie thérapeutique prometteuse contre le glioblastome. Dans la lignée de cette avancée, et compte tenu de l'efficacité démontrée du DV188 dans les modèles murins, l'exploration de sa combinaison avec l'agent chimiothérapeutique de référence s'impose comme une nouvelle stratégie synergique potentielle pour le traitement de cette maladie dévastatrice
Glioblastomas are the most aggressive brain tumors, characterized by intratumoral heterogeneity, poor life expectancy, and significant resistance to radio-chemotherapy treatments. The complexity of these tumors is further exacerbated by the presence of glioma stem cells (GSC), which play a crucial role in clonal proliferation, invasiveness, and tumor recurrence. GSC express various stem cell and pluripotency markers, such as NANOG and SOX2. These transcription factors must be translocated into the nucleus to activate gene programs that maintain stemness and tumorigenic properties of GSCs. The conventional treatment involves surgical intervention, when possible, followed by radio- chemotherapy. Unfortunately, this conventional treatment is limited, and tumors relapse due to the selection and the persistence of resistant GSC upon treatment cessation. To overcome this issue resulting from cytotoxic pressure, we aimed to develop a novel therapeutic strategy based on the differentiation of GSC into a less aggressive phenotype that is more sensitive to conventional treatments. In this context, we identified a chemical compound, DV188, synthesized from a molecule library by the Institute of Chemistry in Nice. Our results indicate that this compound effectively induces differentiation of patient-derived GSC, inhibits their clonal proliferation capacity, and sensitizes them to the standard chemotherapeutic agent, temozolomide (TMZ). Importantly, DV188 prevents in vivo tumor initiation and progression without affecting mouse survival following months of treatment. Additionally, the combination of DV188 and TMZ treatment demonstrated twice the efficacy compared to TMZ alone. At the molecular level, we identified an effect of DV188 on the nuclear transport of essential factors required for maintaining stem cell properties, thereby disrupting mechanisms that drive GSC aggressiveness and tumorigenicity. Our data strongly support the idea that targeting GSC differentiation, through the inhibition of nuclear transport of transcription factors involved in maintaining stemness properties, represents a promising therapeutic avenue against glioblastoma. In line with this advancement and considering the demonstrated efficacy of DV188 in murine models, the exploration of its combination with the standard chemotherapeutic agent emerges as a potential new synergistic strategy for treating this devastating disease

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Van, der Watt Pauline Janet. "Expression and regulation of the nuclear transport proteins, Crm1 and Kpnß1, in cervical cancer and transformed cells". Doctoral thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/3152.

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Pradezynski, Fabrine. "Modulation du système interféron de type I par les virus : en particulier par le virus de l'hépatite C et le virus influenza". Thesis, Lyon 1, 2010. http://www.theses.fr/2010LYO10252.

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Afin de se répliquer et de se propager efficacement, les virus ont développé de multiples stratégies leur permettant d’échapper au système de défense innée : le système IFN de type I. Ce travail de thèse a alors consisté à étudier les interactions entre protéines virales et protéines de ce système de défense afin de mieux comprendre les mécanismes de subversion virale et d’identifier d’éventuelles cibles cellulaires thérapeutiques. La reconstruction d’un réseau d’interactions entre ces protéines nous a permis d’identifier des stratégies différentielles de subversion pour 4 familles virales et de montrer un ciblage massif et significatif des protéines du système IFN de type I par les virus. Les protéines en interaction directe avec ces protéines sont également fortement touchées par les virus et sont de potentiels modulateurs du système IFN de type I. Parmi ces modulateurs, le processus biologique sur-représenté est le transport nucléocytoplasmique et la protéine KPNA1 impliquée dans ce processus a retenu notre attention. L’étude fonctionnelle de l’interaction entre la protéine KPNA1 et la protéine NS3 du VHC a montré que la protéine NS3 associée à son cofacteur NS4A inhibe partiellement la réponse IFN de type I en empêchant l’import nucléaire de STAT1. Ce phénotype pourrait résulter de la dégradation de KPNA1 par NS3/4A. Par ailleurs, l’identification de nouveaux inter-acteurs de la protéine NS1 du virus influenza par criblage double-hybride levure a révélé la protéine induite par les IFN de type I, ADAR1, comme partenaire de la protéine NS1 de multiples souches virales et nous avons montré qu'ADAR1 est un facteur pro-viral dont la fonction editing est activée par NS1
To replicate and propagate efficiently, viruses have developed multiple strategies allowing them to escape the innatedefense system: the type I IFN system, This work of thesis then consisted in studying the interactions between viralproteins and proteins of this defence system in order to understand better the mechanisms of viral subversion andidentifY possible therapeutic cellular tatgets. The reconstruction of a network of interacting proteins involved in the typeI IFN system allowed us to identifY differentiai subversion strategies for 4 viral families and to show a massive andsignificant targeting of proteins of the type I IFN system by viruses. Proteins directly interacting with the type Iinterferon system network are also strongly targeted by viruses and are potential modulators of the type I IFN system.Among these modulators, the most tatgeted function conesponds to the transport of NLS-bearing substrates to thenucleus and the KPNAI protein involved in this process held our attention. The functional study of the interactionbetween KPNA1 and NS3 protein of the HCV showed that NS3 protein associated with its cofactor NS4A inhibitsprutially the type I IFN response by preventing the nuclear translocation of ST A Tl. This phenotype could result fromthe degradation of KPNAI by NS3/4A. Besides, the identification of new cellular prutners ofNS 1 prote in of influenzavirus by yeast two-hybrid screens revealed ADARI, an interferon-stimulated prote in, as partner of NS 1 of ali testedvirus strains and we showed that ADARI is an essential host factor for viral replication and its editing function isactivated by NS 1 protein

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Trabalhos de conferências sobre o assunto "Kpnb1"

Park, Chan Hee, Seung Wook Ham, HyeKyoung Shin e Kyung Soo Oh. "Abstract 5138: Inhibition of kPNB1 and NUPR1 binding increase the anti-cancer drug sensitivity". In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-5138.

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Chi, Ru-pin, Wei Wei, Michael Birrer e Virna D. Leaner. "Abstract 1069: Inhibition of the nuclear import receptor, KpnB1 synergizes with cisplatin toxicity in cervical cancer cells". In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-1069.

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Kodama, Michiko, Takahiro Kodama, Kosuke Yoshihara, Kae Hashimoto, Seiji Mabuchi, Kenjiro Sawada, Tadashi Kimura, Neal Copeland e Nancy Jenkins. "Abstract 411:In vivopooled shRNA library identifies KPNB1 as a new drug target for epithelial ovarian cancer". In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-411.

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Stelma, Tamara, Alicia Chi, Anwar Mall, Dhiren Govender e Virna D. Leaner. "Abstract B09: KPNB1-mediated nuclear import is required for inflammatory cytokine expression, invasion and survival of cancer cells". In Abstracts: AACR International Conference: New Frontiers in Cancer Research; January 18-22, 2017; Cape Town, South Africa. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.newfront17-b09.

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Du, Wenwen, Jianjie Zhu, Yuanyuan Zeng, Yang Zhang, Zeyi Liu e Jian-An Huang. "KPNB1-mediated PD-L1 nuclear translocation promotes non-small cell lung cancer cell proliferation via the Gas6/MerTK signalling pathway". In ERS International Congress 2020 abstracts. European Respiratory Society, 2020. http://dx.doi.org/10.1183/13993003.congress-2020.1753.

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Fielhaber, Jill A., Jason Tan, Ortal Attais, Ying Shan Han, Kwang Bo Joung e Arnold S. Kristof. "MTOR Regulates STAT1 Nuclear Trafficking Via KPNA1 In Lung Epithelial Cells". In American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado. American Thoracic Society, 2011. http://dx.doi.org/10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a5112.

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Carden, Sarah, Pauline van der Watt, Patrizia Lavia e Virna Leaner. "Abstract B12: Investigating the specificity of the small molecule inhibitor INI-43 for Kpnβ1 in cancer cells". In Abstracts: AACR International Conference: New Frontiers in Cancer Research; January 18-22, 2017; Cape Town, South Africa. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.newfront17-b12.

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