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Articoli di riviste sul tema "Kpnb1"

Autore: Grafiati

Pubblicato: 29 marzo 2025

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1

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. 6 (dicembre 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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2

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. 8 (27 luglio 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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3

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. 4 (8 aprile 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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4

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. 35 (15 agosto 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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5

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. 1 (19 maggio 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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6

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. 6 (10 marzo 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. 9 (1 maggio 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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8

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. 13 (31 maggio 2016): 1406–9. http://dx.doi.org/10.1002/cmdc.201600159.

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9

Zeng, Renya, e Jixin Dong. "Abstract 5491: Targeting importin-YAP axis in pancreatic ductal adenocarcinoma". Cancer Research 82, n. 12_Supplement (15 giugno 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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10

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. 22 (9 marzo 2018): 2936–52. http://dx.doi.org/10.1038/s41388-018-0180-9.

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11

Sekimoto, Noboru, Yutaka Suzuki e Sumio Sugano. "Decreased KPNB1 Expression is Induced by PLK1 Inhibition and Leads to Apoptosis in Lung Adenocarcinoma". Journal of Cancer 8, n. 19 (2017): 4125–40. http://dx.doi.org/10.7150/jca.21802.

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12

Zhang, Pingyu, Jeannine Garnett, Chad J. Creighton, Ghadah Abbas Al Sannaa, Davis R. Igram, Alexander Lazar, Xiuping Liu, Changgong Liu e Raphael E. Pollock. "EZH2-miR-30d-KPNB1 pathway regulates malignant peripheral nerve sheath tumour cell survival and tumourigenesis". Journal of Pathology 232, n. 3 (13 gennaio 2014): 308–18. http://dx.doi.org/10.1002/path.4294.

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13

Ha, Siyoung, Jiwon Oh, Ji Min Jang, Dae Kyong Kim e Seung Wook Ham. "Synthesis and Biological Evaluation of 2-Aminothiazole Derivative Having Anticancer Activity as a KPNB1 Inhibitor". Bulletin of the Korean Chemical Society 37, n. 11 (4 ottobre 2016): 1743–44. http://dx.doi.org/10.1002/bkcs.10968.

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14

Dai, Aihua, Xiaorong Liu, Yu Zhang, Lijian Han, Liang Zhu, Haidan Ni, Rongrong Chen e Maohong Cao. "RETRACTED ARTICLE: Up-Regulation of KPNB1 Involves in Neuronal Apoptosis Following Intracerebral Hemorrhage in Adult Rats". Neurochemical Research 40, n. 11 (25 agosto 2015): 2177–87. http://dx.doi.org/10.1007/s11064-015-1706-y.

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15

Liu, Jun‐Chao, Dong‐Fang Xue, Xiao‐Qian Wang, Deng‐Bin Ai e Pei‐Juan Qin. "MiR‐101 relates to chronic peripheral neuropathic pain through targeting KPNB1 and regulating NF‐κB signaling". Kaohsiung Journal of Medical Sciences 35, n. 3 (marzo 2019): 139–45. http://dx.doi.org/10.1002/kjm2.12025.

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16

Wang, Teng, Zhenglan Huang, Ningshu Huang, Yuhang Peng, Miao Gao, Xin Wang e Wenli Feng. "Inhibition of KPNB1 Inhibits Proliferation and Promotes Apoptosis of Chronic Myeloid Leukemia Cells Through Regulation of E2F1". OncoTargets and Therapy Volume 12 (dicembre 2019): 10455–67. http://dx.doi.org/10.2147/ott.s210048.

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17

Stelma, Tamara, e Virna D. Leaner. "KPNB1-mediated nuclear import is required for motility and inflammatory transcription factor activity in cervical cancer cells". Oncotarget 8, n. 20 (2 marzo 2017): 32833–47. http://dx.doi.org/10.18632/oncotarget.15834.

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Dai, Aihua, Xiaorong Liu, Yu Zhang, Lijian Han, Liang Zhu, Haidan Ni, Rongrong Chen e Maohong Cao. "Retraction Note to: Up-Regulation of KPNB1 Involves in Neuronal Apoptosis Following Intracerebral Hemorrhage in Adult Rats". Neurochemical Research 41, n. 6 (13 aprile 2016): 1505. http://dx.doi.org/10.1007/s11064-016-1860-x.

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García-Cárdenas, Jennyfer M., Isaac Armendáriz-Castillo, Andy Pérez-Villa, Alberto Indacochea, Andrea Jácome-Alvarado, Andrés López-Cortés e Santiago Guerrero. "Integrated In Silico Analyses Identify PUF60 and SF3A3 as New Spliceosome-Related Breast Cancer RNA-Binding Proteins". Biology 11, n. 4 (22 marzo 2022): 481. http://dx.doi.org/10.3390/biology11040481.

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Abstract (sommario):

More women are diagnosed with breast cancer (BC) than any other type of cancer. Although large-scale efforts have completely redefined cancer, a cure remains unattainable. In that respect, new molecular functions of the cell should be investigated, such as post-transcriptional regulation. RNA-binding proteins (RBPs) are emerging as critical post-transcriptional modulators of tumorigenesis, but only a few have clear roles in BC. To recognize new putative breast cancer RNA-binding proteins, we performed integrated in silico analyses of all human RBPs (n = 1392) in three major cancer databases and identified five putative BC RBPs (PUF60, TFRC, KPNB1, NSF, and SF3A3), which showed robust oncogenic features related to their genomic alterations, immunohistochemical changes, high interconnectivity with cancer driver genes (CDGs), and tumor vulnerabilities. Interestingly, some of these RBPs have never been studied in BC, but their oncogenic functions have been described in other cancer types. Subsequent analyses revealed PUF60 and SF3A3 as central elements of a spliceosome-related cluster involving RBPs and CDGs. Further research should focus on the mechanisms by which these proteins could promote breast tumorigenesis, with the potential to reveal new therapeutic pathways along with novel drug-development strategies.

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Dong, Qiang, Xiang Li, Cheng-Zhi Wang, Shaohua Xu, Gang Yuan, Wei Shao, Baodong Liu et al. "Roles of the CSE1L-mediated nuclear import pathway in epigenetic silencing". Proceedings of the National Academy of Sciences 115, n. 17 (10 aprile 2018): E4013—E4022. http://dx.doi.org/10.1073/pnas.1800505115.

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Epigenetic silencing can be mediated by various mechanisms, and many regulators remain to be identified. Here, we report a genome-wide siRNA screening to identify regulators essential for maintaining gene repression of a CMV promoter silenced by DNA methylation. We identified CSE1L (chromosome segregation 1 like) as an essential factor for the silencing of the reporter gene and many endogenous methylated genes. CSE1L depletion did not cause DNA demethylation. On the other hand, the methylated genes derepressed by CSE1L depletion largely overlapped with methylated genes that were also reactivated by treatment with histone deacetylase inhibitors (HDACi). Gene silencing defects observed upon CSE1L depletion were linked to its nuclear import function for certain protein cargos because depletion of other factors involved in the same nuclear import pathway, including KPNAs and KPNB1 proteins, displayed similar derepression profiles at the genome-wide level. Therefore, CSE1L appears to be critical for the nuclear import of certain key repressive proteins. Indeed, NOVA1, HDAC1, HDAC2, and HDAC8, genes known as silencing factors, became delocalized into cytosol upon CSE1L depletion. This study suggests that the cargo specificity of the protein nuclear import system may impact the selectivity of gene silencing.

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Zhang, Pingyu, Xianbin Yang, Xiaoyan Ma, Davis R. Ingram, Alexander J. Lazar, Keila E. Torres e Raphael E. Pollock. "Antitumor effects of pharmacological EZH2 inhibition on malignant peripheral nerve sheath tumor through the miR-30a and KPNB1 pathway". Molecular Cancer 14, n. 1 (2015): 55. http://dx.doi.org/10.1186/s12943-015-0325-1.

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Schertzer, Michael, Laurent Jullien, André L. Pinto, Rodrigo T. Calado, Patrick Revy e Arturo Londoño-Vallejo. "Human RTEL1 Interacts with KPNB1 (Importin β) and NUP153 and Connects Nuclear Import to Nuclear Envelope Stability in S-Phase". Cells 12, n. 24 (8 dicembre 2023): 2798. http://dx.doi.org/10.3390/cells12242798.

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Regulator of TElomere Length Helicase 1 (RTEL1) is a helicase required for telomere maintenance and genome replication and repair. RTEL1 has been previously shown to participate in the nuclear export of small nuclear RNAs. Here we show that RTEL1 deficiency leads to a nuclear envelope destabilization exclusively in cells entering S-phase and in direct connection to origin firing. We discovered that inhibiting protein import also leads to similar, albeit non-cell cycle-related, nuclear envelope disruptions. Remarkably, overexpression of wild-type RTEL1, or of its C-terminal part lacking the helicase domain, protects cells against nuclear envelope anomalies mediated by protein import inhibition. We identified distinct domains in the C-terminus of RTEL1 essential for the interaction with KPNB1 (importin β) and NUP153, respectively, and we demonstrated that, on its own, the latter domain can promote the dynamic nuclear internalization of peptides that freely diffuse through the nuclear pore. Consistent with putative functions exerted in protein import, RTEL1 can be visualized on both sides of the nuclear pore using high-resolution microscopy. In all, our work points to an unanticipated, helicase-independent, role of RTEL1 in connecting both nucleocytoplasmic trafficking and nuclear envelope integrity to genome replication initiation in S-phase.

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Wang, Lixin, Bishal Paudel, Anthony McKnight e Kevin Janes. "Abstract 2565: Divergentnucleocytoplasmic transport influences escape from HER2-activated DCIS-like state". Cancer Research 83, n. 7_Supplement (4 aprile 2023): 2565. http://dx.doi.org/10.1158/1538-7445.am2023-2565.

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Abstract HER2/ErbB2 and EGFR/ErbB1 activation incite a phenotype resembling premalignant escape from ductal carcinoma in situ (DCIS) in the 3D multicellular arrangement of breast-epithelial cells. This phenomenon tends to be infrequent, and the exact mechanism for its heterogeneous presentation has been elusive. We sought to investigate the process by which ErbB receptors facilitate a picture of incomplete penetrance in DCIS escape (DE). To identify the transcriptional signatures that prime cells towards DE, we randomly profiled 10-cell transcriptomes of single spheroids after 24 hours of ERBB activation, and frequency matched gene expression to the DE-phenotype. We uncovered a network of nucleocytoplasmic transport (NCT) regulators that alter the DE-phenotype penetrance. Of the regulators, CSE1L (an exportin) synergistically increases the DE-frequency when induced, while its knockdown reduces the phenotype, suggesting its functional role. Furthermore, we evaluated the significance of this result in vivo by perturbing Cse1l in Erbb2-amplified mouse mammary-gland tumors and found that activation of Erbb2 (mimicked by ERBB-inhibitor release) alters the macroscale organization of tumors, reminiscent of DE. Specifically, we found an elevated CSE1L inhibits an accumulation of classical nuclear-localizing cargoes that require binding with importin-α/β (KPNAs, KPNB1) complexes. Using proximity labeling with BirA*-fused with CSE1L, we identified ERBB1/ERBB2/ERBB4 as CSE1L interactors. Mechanistically, hetero-dimerized ERBB receptors interact with importin-α/β complexes and re-localize to the nucleus, corroborating previous observations of receptors’ nuclear translocation. Intriguingly, we observed that Doxycycline-induced knockdown of clathrin heavy chain (CLTC, involved in intracellular trafficking of receptors via endocytosis) synergizes with ERBB activation to increase the DE-phenotype penetrance. Using ChIP-Seq, we found that ERBB1 binds to the locus of microRNA, miR205, which negatively regulates the expression of importin-α, mainly KPNA1. These results indicate that ERBB receptors translocated to the nucleus reduce the DE-phenotype by inhibiting importins via miR205, while CSE1L induction relieves this inhibition by reducing the receptor's nuclear accumulation. Taken together, these results show that nucleocytoplasmic shuttling of receptors in ERBB-active breast epithelia generates tunable cross-inhibitory feedback through nucleocytoplasmic transport that results in long-term, heterogeneous multicellular fates. Citation Format: Lixin Wang, Bishal Paudel, Anthony McKnight, Kevin Janes. Divergentnucleocytoplasmic transport influences escape from HER2-activated DCIS-like state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2565.

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Segatori, Valeria Inés, Juan Garona, Lorena Grisel Caligiuri, Juan Bizzotto, Rosario Lavignolle, Ayelén Toro, Pablo Sanchis et al. "Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients". Viruses 13, n. 10 (15 ottobre 2021): 2084. http://dx.doi.org/10.3390/v13102084.

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Nuclear transport and vesicle trafficking are key cellular functions involved in the pathogenesis of RNA viruses. Among other pleiotropic effects on virus-infected host cells, ivermectin (IVM) inhibits nuclear transport mechanisms mediated by importins and atorvastatin (ATV) affects actin cytoskeleton-dependent trafficking controlled by Rho GTPases signaling. In this work, we first analyzed the response to infection in nasopharyngeal swabs from SARS-CoV-2-positive and -negative patients by assessing the gene expression of the respective host cell drug targets importins and Rho GTPases. COVID-19 patients showed alterations in KPNA3, KPNA5, KPNA7, KPNB1, RHOA, and CDC42 expression compared with non-COVID-19 patients. An in vitro model of infection with Poly(I:C), a synthetic analog of viral double-stranded RNA, triggered NF-κB activation, an effect that was halted by IVM and ATV treatment. Importin and Rho GTPases gene expression was also impaired by these drugs. Furthermore, through confocal microscopy, we analyzed the effects of IVM and ATV on nuclear to cytoplasmic importin α distribution, alone or in combination. Results showed a significant inhibition of importin α nuclear accumulation under IVM and ATV treatments. These findings confirm transcriptional alterations in importins and Rho GTPases upon SARS-CoV-2 infection and point to IVM and ATV as valid drugs to impair nuclear localization of importin α when used at clinically-relevant concentrations.

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Wang, Jinglei, Hanying Chen, Yongsheng Zhang, Song Jiang, Xiancun Zeng e Hong Shen. "Comprehensive Analysis of Differentially Expressed CircRNAs in the Ovaries of Low- and High-Fertility Sheep". Animals 13, n. 2 (9 gennaio 2023): 236. http://dx.doi.org/10.3390/ani13020236.

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Abstract (sommario):

CircRNAs are essential in regulating follicle growth and development and the female reproductive system at multiple levels. However, the molecular mechanism by which circRNAs regulate reproduction in sheep is unclear and requires further exploration. In this study, RNA sequencing was performed to reveal the circRNA expression profiles in the ovaries of Cele black sheep and Hetian sheep during estrus. Analysis of the number of circRNAs in their host genes revealed that 5031 genes could produce 20,835 circRNAs. Among the differentially expressed circRNAs (DEcircRNA), 75 were upregulated, and 105 were downregulated. Functional enrichment analysis showed that the host genes of DEcircRNA were involved in several pathways, including the MAPK and Hippo signaling pathway. In addition, we constructed a subnetwork of competitive endogenous RNA (ceRNA) containing 4 mRNAs, 4 microRNAs (miRNAs), and 10 circRNAs, potentially related to follicle development. Functional circRNAs (e.g., novel_circ_0003851, novel_circ_0015526, novel_circ_0008117) were found to act as ceRNAs for follicle growth and development-related mRNAs (CUEDC1, KPNB1, ZFPM2) by sponging functional miRNAs (miR-29a, miR-29b, miR-17-5p). Finally, through an RNA pull-down assay, oar-miR-125b was selected and confirmed as the target miRNA of novel-circ-0041512. We analyzed the overall expression of circRNAs in sheep ovaries. Further, we explored the potential mechanisms underlying the circRNA functions, providing a theoretical basis for the genetic progress of reproductive traits in sheep.

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26

Ye, Qing, e Nancy Lan Guo. "Hub Genes in Non-Small Cell Lung Cancer Regulatory Networks". Biomolecules 12, n. 12 (29 novembre 2022): 1782. http://dx.doi.org/10.3390/biom12121782.

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Abstract (sommario):

There are currently no accurate biomarkers for optimal treatment selection in early-stage non-small cell lung cancer (NSCLC). Novel therapeutic targets are needed to improve NSCLC survival outcomes. This study systematically evaluated the association between genome-scale regulatory network centralities and NSCLC tumorigenesis, proliferation, and survival in early-stage NSCLC patients. Boolean implication networks were used to construct multimodal networks using patient DNA copy number variation, mRNA, and protein expression profiles. T statistics of differential gene/protein expression in tumors versus non-cancerous adjacent tissues, dependency scores in in vitro CRISPR-Cas9/RNA interference (RNAi) screening of human NSCLC cell lines, and hazard ratios in univariate Cox modeling of the Cancer Genome Atlas (TCGA) NSCLC patients were correlated with graph theory centrality metrics. Hub genes in multi-omics networks involving gene/protein expression were associated with oncogenic, proliferative potentials and poor patient survival outcomes (p < 0.05, Pearson’s correlation). Immunotherapy targets PD1, PDL1, CTLA4, and CD27 were ranked as top hub genes within the 10th percentile in most constructed multi-omics networks. BUB3, DNM1L, EIF2S1, KPNB1, NMT1, PGAM1, and STRAP were discovered as important hub genes in NSCLC proliferation with oncogenic potential. These results support the importance of hub genes in NSCLC tumorigenesis, proliferation, and prognosis, with implications in prioritizing therapeutic targets to improve patient survival outcomes.

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27

Wang, Nianwu, Wei Wang, Wenli Mao, Nazuke Kuerbantayi, Nuan Jia, Yan Chen, Fang Zhou, Li Yin e Yukun Wang. "RBBP4 Enhances Platinum Chemo Resistance in Lung Adenocarcinoma". BioMed Research International 2021 (9 gennaio 2021): 1–21. http://dx.doi.org/10.1155/2021/6905985.

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Abstract (sommario):

Background. The majority of lung cancers are adenocarcinomas, with the proportion being 40%. The patients are mostly diagnosed in the middle and late stages with metastasis and easy recurrence, which poses great challenge to the treatment and prognosis. Platinum-based chemotherapy is a primary treatment for adenocarcinoma, which frequently causes drug resistance. As a result, it is important to uncover the mechanisms of the chemoresponse of adenocarcinoma to platinum-based chemotherapy. Methods. The genes from the dataset GSE7880 were gathered into gene modules with the assistance of weighted gene coexpression network analysis (WGCNA), the gene trait significance absolute value (|GS|), and gene module memberships (MM). The genes from hub gene modules were calculated with a protein-protein interaction (PPI) network analysis in order to obtain a screening map of hub genes. The hub genes with both a high |GS| and MM and a high degree were selected. Furthermore, genes in the hub gene modules also went through a Gene Ontology (GO) functional enrichment analysis. Results. 11 hub genes in four hub gene modules (LY86, ACTR2, CDK2, CKAP4, KPNB1, RBBP4, SMAD4, MYL6, RPS27, TSPAN2, and VAMP2) were chosen as the significant hub genes. Through the GO function enrichment analysis, it was indicated that four modules were abundant in immune system functions (floralwhite), amino acid biosynthetic process (lightpink4), cell chemotaxis (navajowhite2), and targeting protein (paleturquoise). Four hub genes with the highest |GS| were verified by prognostic analysis.

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28

Zhen, Yan, Vigdis Sørensen, Camilla S. Skjerpen, Ellen M. Haugsten, Yixin Jin, Sebastien Wälchli, Sjur Olsnes e Antoni Wiedlocha. "Nuclear Import of Exogenous FGF1 Requires the ER-Protein LRRC59 and the Importins Kpnα1 and Kpnβ1". Traffic 13, n. 5 (4 marzo 2012): 650–64. http://dx.doi.org/10.1111/j.1600-0854.2012.01341.x.

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29

Thiel, Cora Sandra, Swantje Christoffel, Svantje Tauber, Christian Vahlensieck, Diane de Zélicourt, Liliana E. Layer, Beatrice Lauber, Jennifer Polzer e Oliver Ullrich. "Rapid Cellular Perception of Gravitational Forces in Human Jurkat T Cells and Transduction into Gene Expression Regulation". International Journal of Molecular Sciences 21, n. 2 (14 gennaio 2020): 514. http://dx.doi.org/10.3390/ijms21020514.

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Abstract (sommario):

Cellular processes are influenced in many ways by changes in gravitational force. In previous studies, we were able to demonstrate, in various cellular systems and research platforms that reactions and adaptation processes occur very rapidly after the onset of altered gravity. In this study we systematically compared differentially expressed gene transcript clusters (TCs) in human Jurkat T cells in microgravity provided by a suborbital ballistic rocket with vector-averaged gravity (vag) provided by a 2D clinostat. Additionally, we included 9× g centrifuge experiments and rigorous controls for excluding other factors of influence than gravity. We found that 11 TCs were significantly altered in 5 min of flight-induced and vector-averaged gravity. Among the annotated clusters were G3BP1, KPNB1, NUDT3, SFT2D2, and POMK. Our results revealed that less than 1% of all examined TCs show the same response in vag and flight-induced microgravity, while 38% of differentially regulated TCs identified during the hypergravity phase of the suborbital ballistic rocket flight could be verified with a 9× g ground centrifuge. In the 2D clinostat system, doing one full rotation per second, vector effects of the gravitational force are only nullified if the sensing mechanism requires 1 s or longer. Due to the fact that vag with an integration period of 1 s was not able to reproduce the results obtained in flight-induced microgravity, we conclude that the initial trigger of gene expression response to microgravity requires less than 1 s reaction time. Additionally, we discovered extensive gene expression differences caused by simple handling of the cell suspension in control experiments, which underlines the need for rigorous standardization regarding mechanical forces during cell culture experiments in general.

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30

Ayala-Madrigal, M. L., S. Doerr, M. L. Ramírez-Dueñas e I. Hansmann. "Assignment¹ of KPNA4 and KPNB1 encoding karyopherin alpha 4 and beta 1 to human chromosome bands 11q22 and 17q21 respectively, by in situ hybridization". Cytogenetic and Genome Research 89, n. 3-4 (2000): 258–59. http://dx.doi.org/10.1159/000015627.

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31

Sakurai, Koki, Taichi Itou, Makiko Morita, Emiko Kasahara, Tetsuji Moriyama, Tom Macpherson, Takaaki Ozawa et al. "Effects of Importin α1/KPNA1 deletion and adolescent social isolation stress on psychiatric disorder-associated behaviors in mice". PLOS ONE 16, n. 11 (12 novembre 2021): e0258364. http://dx.doi.org/10.1371/journal.pone.0258364.

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Abstract (sommario):

Importin α1/KPNA1 is a member of the Importin α family widely present in the mammalian brain and has been characterized as a regulator of neuronal differentiation, synaptic functionality, and anxiety-like behavior. In humans, a de novo mutation of the KPNA1 (human Importin α5) gene has been linked with schizophrenia; however, the precise roles of KPNA1 in disorder-related behaviors are still unknown. Moreover, as recent studies have highlighted the importance of gene-environment interactions in the development of psychiatric disorders, we investigated the effects of Kpna1 deletion and social isolation stress, a paradigm that models social stress factors found in human patients, on psychiatric disorder-related behaviors in mice. Through assessment in a behavioral battery, we found that Kpna1 knockout resulted in the following behavioral phenotype: (1) decreased anxiety-like behavior in an elevated plus maze test, (2) short term memory deficits in novel object recognition test (3) impaired sensorimotor gating in a prepulse inhibition test. Importantly, exposure to social isolation stress resulted in additional behavioral abnormalities where isolated Kpna1 knockout mice exhibited: (1) impaired aversive learning and/or memory in the inhibitory avoidance test, as well as (2) increased depression-like behavior in the forced swim test. Furthermore, we investigated whether mice showed alterations in plasma levels of stress-associated signal molecules (corticosterone, cytokines, hormones, receptors), and found that Kpna1 knockout significantly altered levels of corticosterone and LIX (CXCL5). Moreover, significant decreases in the level of prolactin were found in all groups except for group-housed wild type mice. Our findings demonstrate that Kpna1 deletion can trigger widespread behavioral abnormalities associated with psychiatric disorders, some of which were further exacerbated by exposure to adolescent social isolation. The use of Kpna1 knockout mice as a model for psychiatric disorders may show promise for further investigation of gene-environment interactions involved in the pathogenesis of psychiatric disorders.

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32

Balcão, Victor M., Fernanda C. Moreli, Erica C. Silva, Bianca G. Belline, Layla F. Martins, Fernando P. N. Rossi, Carla Pereira, Marta M. D. C. Vila e Aline M. da Silva. "Isolation and Molecular Characterization of a Novel Lytic Bacteriophage That Inactivates MDR Klebsiella pneumoniae Strains". Pharmaceutics 14, n. 7 (6 luglio 2022): 1421. http://dx.doi.org/10.3390/pharmaceutics14071421.

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Abstract (sommario):

The worldwide increase in serious infections caused by multidrug-resistant (MDR) K. pneumoniae emphasizes the urgent need of new therapeutic strategies for the control of this pathogen. There is growing interest in the use of bacteriophages (or phages) to treat K. pneumoniae infections, and newly isolated phages are needed. Here, we report the isolation and physical/biological/molecular characterization of a novel lytic phage and its efficacy in the control of MDR K. pneumoniae. The phage vB_KpnS_Uniso31, referred to hereafter as phage Kpn31, was isolated from hospital wastewater using K. pneumoniae CCCD-K001 as the host. Phage Kpn31 presents a siphovirus-like morphotype and was classified as Demerecviridae; Sugarlandvirus based on its complete genome sequence. The 113,444 bp Kpn31 genome does not encode known toxins or antimicrobial resistance genes, nor does it encode depolymerases related sequences. Phage Kpn31 showed an eclipse time of 15 min and a burst size of 9.12 PFU/host cell, allowing us to conclude it replicates well in K. pneumoniae CCCD-K001 with a latency period of 30 min. Phage Kpn31 was shown to be effective against at least six MDR K. pneumoniae clinical isolates in in vitro antibacterial activity assays. Based on its features, phage Kpn31 has potential for controlling infections caused by MDR K. pneumoniae.

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33

Jones, Jessica M., Carrie Simkus e Anamika Bhattacharyya. "KPNA1 is a putative substrate of the RAG1 ubiquitin ligase (138.11)". Journal of Immunology 182, n. 1_Supplement (1 aprile 2009): 138.11. http://dx.doi.org/10.4049/jimmunol.182.supp.138.11.

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Abstract (sommario):

Abstract The RAG1 V(D)J recombinase encompasses DNA binding/cleavage and ubiquitin ligase activities. The nuclear transport protein karyopherin alpha 1 (KPNA1) binds to RAG1 upstream of its ubiquitin ligase domain, but this interaction is not required for nuclear localization of RAG1. We found that the isolated ubiquitin ligase domain of RAG1 (amino acids 218-389) promoted ubiquitylation of purified KPNA1 in a reaction supported by the ubiquitin conjugating (E2) enzyme UbcH2/Rad6 or UbcH5a. KPNA1 is the first putative substrate identified for the RAG1 ubiquitin ligase. Ubiquitylation of KPNA1 required the lysine/arginine-rich region spanning RAG1 amino acids 218-263 upstream of the RAG1 ubiquitin ligase domain, but RAG1 was still able to undergo auto-ubiquitylation in this region even in the presence of KPNA1. RAG1 did not promote rapid ubiquitin chain extension following mono-ubiquitylation of substrate, regardless of the E2 used. Substitutions of amino acids surrounding the third, non-canonical Zn coordination site of the RAG1 RING domain abrogated functional interaction with E2 enzymes, and this was significantly correlated with reduction in the ability of full length RAG1 to support recombination of extra-chromosomal substrates. These data suggest that RAG1-dependent mono-ubiquitylation of a substrate, possibly KPNA1, is required for optimal levels of V(D)J recombination.

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34

Spruit, Cindy M., Anu Wicklund, Xing Wan, Mikael Skurnik e Maria I. Pajunen. "Discovery of Three Toxic Proteins of Klebsiella Phage fHe-Kpn01". Viruses 12, n. 5 (15 maggio 2020): 544. http://dx.doi.org/10.3390/v12050544.

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Abstract (sommario):

The lytic phage, fHe-Kpn01 was isolated from sewage water using an extended-spectrum beta-lactamase-producing strain of Klebsiella pneumoniae as a host. The genome is 43,329 bp in size and contains direct terminal repeats of 222 bp. The genome contains 56 predicted genes, of which proteomics analysis detected 29 different proteins in purified phage particles. Comparison of fHe-Kpn01 to other phages, both morphologically and genetically, indicated that the phage belongs to the family Podoviridae and genus Drulisvirus. Because fHe-Kpn01 is strictly lytic and does not carry any known resistance or virulence genes, it is suitable for phage therapy. It has, however, a narrow host range since it infected only three of the 72 tested K. pneumoniae strains, two of which were of capsule type KL62. After annotation of the predicted genes based on the similarity to genes of known function and proteomics results on the virion-associated proteins, 22 gene products remained annotated as hypothetical proteins of unknown function (HPUF). These fHe-Kpn01 HPUFs were screened for their toxicity in Escherichia coli. Three of the HPUFs, encoded by the genes g10, g22, and g38, were confirmed to be toxic.

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35

Nomiya, Hirotaka, e Masami Yamada. "Interactions between genetic and environmental factors and schizophrenia: Insights from KPNA1-deficient mice". Journal of Neurology & Neuromedicine 8, n. 2 (14 maggio 2024): 1–2. http://dx.doi.org/10.29245/2572.942x/2024/2.1299.

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Abstract (sommario):

The interactions between genetic and environmental factors (G x E interactions) play a crucial role in the pathogenesis of schizophrenia. The administration of phencyclidine, a psychotropic drug, to Kpna1-deficient mice induces behavioral abnormalities resembling schizophrenia. In the nucleus accumbens of these mice, the expressions of dopamine receptors, an RNA editing enzyme, and cytoplasmic dynein demonstrate gene-environment interaction-dependent alterations. Kpna1-deficient mice may be useful as a gene-environment interaction model for schizophrenia and provide insights into its pathogenesis. Further, changes in gene expression in the nucleus accumbens may be involved in the development of schizophrenia.

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36

Wang, X., L. Magnani e R. Cabot. "198 KARYOPHERIN ALPHA EXPRESSION IN PORCINE OOCYTES AND EMBRYOS PRODUCED BY IN VITRO FERTILIZATION". Reproduction, Fertility and Development 21, n. 1 (2009): 197. http://dx.doi.org/10.1071/rdv21n1ab198.

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Abstract (sommario):

Partitioning intracellular proteins between nuclear and cytoplasmic compartments is critically important for coordinating major cellular events involved in transcription and differentiation. Import of cytoplasmic proteins bearing classical nuclear localization signals (NLSs) into the nucleus is mediated by the importin α/β heterodimer. Importin α, also called karyopherin α (KPNA), serves to recognize the NLS-bearing cytoplasmic cargo. Six KPNA molecules have been characterized in human (KPNA1-6). Select KPNA molecules are known to be differently expressed in specific tissues; individual KPNA molecules also have specificity for unique NLS-bearing cargos. We hypothesized that transcripts for individual porcine KPNA molecules would be present at differing levels at specific stages of oocyte maturation and cleavage development, thereby reflecting the changing requirements for particular import pathways during this window of development. To test this hypothesis, we first identified the porcine orthologs of KPNA1-6. We also identified the open reading frame of a potentially novel KPNA, KPNA7. KPNA7 was highly represented in the porcine EST database from expressed sequence tags derived from oocytes and ovarian tissue. Transcript abundance of KPNA1-7 was determined in germinal vesicle (GV) and MII-stage (MII) porcine oocytes and 4-cell (4C) and blastocyst-stage (BL) porcine embryos using quantitative real-time PCR. mRNA was isolated from pools (50 200) of GV and MII oocytes and 4C and BL embryos produced by IVF. Transcripts for KPNA1-7 and YWHAG (internal control for transcript normalization) were amplified in duplicate across 3 to 5 replicates. Relative transcript abundance of these genes was measured using the comparative CT method; GV was taken as the calibrator stage. Data were analyzed using GLM procedures in SAS (SAS Institute Inc., Cary, NC, USA) with the significance level at 0.05, and differences were compared by Tukey’s post test. Our results showed that KPNA1 had a significant decrease in MII oocytes (4-fold, GV v. MII). Transcript abundance of KPNA2 was significantly higher in GV oocytes and 4C embryos than in MII oocytes (2-fold GV v. MII; 3-fold 4C v. MII); KPNA2 transcripts were not detectable in BL embryos. KPNA3 transcripts were reduced in BL embryos compared to GV oocytes (8-fold, BL v. GV). KPNA4 transcripts were increased at the 4-cell stage (18-fold, GV v. 4C). The transcripts of KPNA5 were detectable only in GV and MII oocytes. No significant changes in the amount of KPNA6 transcripts were detectable at the stages analyzed. Transcript levels of KPNA7 were reduced in BL embryos as compared to the GV oocytes (1165-fold, BL v. GV). Throughout all these stages examined, KPNA5 had the lowest transcript abundance and was not detectable in 4C and BL stages. Transcripts levels of KPNA7 were in higher abundance than KPNA1-6 in GV and MII oocytes. Results suggest that KPNA7 is a new member of the KPNA family. Our results also suggest that porcine oocytes and embryos, at discrete stages of development, have differing requirements for individual KPNA molecules.

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37

Wei, Jun, e Gwynneth P. Hemmings. "The KPNB3 locus is associated with schizophrenia". Neuroscience Letters 368, n. 3 (settembre 2004): 323–26. http://dx.doi.org/10.1016/j.neulet.2004.07.049.

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38

Wang, Huanru, Meng Yuan, Shuaibo Wang, Li Zhang, Rui Zhang, Xue Zou, Xiaohui Wang, Deyan Chen e Zhiwei Wu. "STAT3 Regulates the Type I IFN-Mediated Antiviral Response by Interfering with the Nuclear Entry of STAT1". International Journal of Molecular Sciences 20, n. 19 (30 settembre 2019): 4870. http://dx.doi.org/10.3390/ijms20194870.

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Abstract (sommario):

Signal transducer and activator of transcription 3 (STAT3) is a multifunctional factor that regulates inflammation and immunity. Knowledge of its regulatory mechanisms is very limited. Here, we showed that enterovirus 71 (EV71) infection induced the phosphorylation of STAT3 and the expression of its downstream inflammatory regulators. Knockdown of STAT3 with siRNAs significantly restricted viral RNA and protein levels, and also reduced viral titers. With further investigation, we found that importin α family member Karyopherin-α1 (KPNA1) was employed by both STAT1 and STAT3 for their nuclear import. The phosphorylated and un-phosphorylated STAT3 competed with STAT1 for binding to the decreased KPNA1 post infection and repressed downstream ISG expression. STAT3 knockdown alleviated the repressed type I IFN-mediated antiviral response upon infection and led to decreased viral replication. Taken together, our data suggested the role of STAT3 in maintaining the balance of inflammation and antiviral responses in the central nervous system (CNS) upon infection.

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39

Holubec, Johannes. "Neue Dimension für die Online-Prozesskontrolle". Wochenblatt für Papierfabrikation 152, n. 6-7 (2024): 29–33. http://dx.doi.org/10.51202/0043-7131-2024-6-7-029.

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Abstract (sommario):

Die Firma Pixact wurde im Jahr 2006 aus universitärem Umfeld in Tampere gegründet und hat sich mittlerweile zu einem weltweit agierenden Unternehmen, mit über 200 installierten Systemen plus 200 Messkampanien, etabliert. Autor: Johannes Holubec, KPNB

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40

Holubec, Johannes. "Neue Dimension für die Online-Prozesskontrolle". Wochenblatt für Papierfabrikation 152, n. 6 (2024): 29–33. http://dx.doi.org/10.51202/0043-7131-2024-6-029.

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Abstract (sommario):

Die Firma Pixact wurde im Jahr 2006 aus universitärem Umfeld in Tampere gegründet und hat sich mittlerweile zu einem weltweit agierenden Unternehmen, mit über 200 installierten Systemen plus 200 Messkampanien, etabliert. Autor: Johannes Holubec, KPNB

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41

Buschmeier, Nicole, e Donato Cristaldi. "Rückgewinnung von Energie und Wasser". Wochenblatt für Papierfabrikation 152, n. 6-7 (2024): 38–39. http://dx.doi.org/10.51202/0043-7131-2024-6-7-038.

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Abstract (sommario):

Die Anaergia Technologies ist Tochter der Anaergia Gruppe mit Sitz in Kanada, einem der Weltmarktführer in der Rückgewinnung von Organik zur Erzeugung von Energie, Wasser und Düngemittel aus nahezu jedem Abfallstrom. Autoren: Nicole Buschmeier, KPNB; Donato Cristaldi, Geschäftsführer Anaergia Technologies GmbH

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42

Buschmeier, Nicole, e Donato Cristaldi. "Rückgewinnung von Energie und Wasser". Wochenblatt für Papierfabrikation 152, n. 6 (2024): 38–39. http://dx.doi.org/10.51202/0043-7131-2024-6-038.

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Abstract (sommario):

Die Anaergia Technologies ist Tochter der Anaergia Gruppe mit Sitz in Kanada, einem der Weltmarktführer in der Rückgewinnung von Organik zur Erzeugung von Energie, Wasser und Düngemittel aus nahezu jedem Abfallstrom. Autoren: Nicole Buschmeier, KPNB; Donato Cristaldi, Geschäftsführer Anaergia Technologies GmbH

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43

Buschmeier, Nicole. "Qualitätsseile seit 1949". Wochenblatt für Papierfabrikation 152, n. 6-7 (2024): 40–42. http://dx.doi.org/10.51202/0043-7131-2024-6-7-040.

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Abstract (sommario):

Lanex a.s. ist tschechischer Hersteller von Qualitätsseilen und ein zuverlässiger Geschäftspartner mit langer Tradition – die ersten Seile wurden in Bolatice bereits im Jahre 1949 hergestellt. Heute stellt Lanex nicht nur Seile und Fasern her, sondern entwickeln sie auch selbst. Autorin: Nicole Buschmeier, KPNB

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44

Buschmeier, Nicole. "Qualitätsseile seit 1949". Wochenblatt für Papierfabrikation 152, n. 6 (2024): 40–42. http://dx.doi.org/10.51202/0043-7131-2024-6-040.

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Abstract (sommario):

Lanex a.s. ist tschechischer Hersteller von Qualitätsseilen und ein zuverlässiger Geschäftspartner mit langer Tradition – die ersten Seile wurden in Bolatice bereits im Jahre 1949 hergestellt. Heute stellt Lanex nicht nur Seile und Fasern her, sondern entwickeln sie auch selbst. Autorin: Nicole Buschmeier, KPNB

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45

Kallioranta, Annely, e Nicole Buschmeier. "Qualitätsleitsysteme für die Papierindustrie". Wochenblatt für Papierfabrikation 152, n. 6-7 (2024): 26–28. http://dx.doi.org/10.51202/0043-7131-2024-6-7-026.

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Abstract (sommario):

Tasowheel ist ein finnisches Familienunternehmen, das 1979 gegründet wurde und sich auf schlüsselfertige QLS-Projekte für Papierherstelleung und Papierverarbeitung spezialisiert hat. Das Unternehmen ist ein unabhängiger Originalhersteller mit agilen und flexiblen Abläufen, der wettbewerbsfähige Produkte anbietet. Autoren: Annely Kallioranta,Tasowheel Oy; Nicole Buschmeier, KPNB

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46

Kallioranta, Annely, e Nicole Buschmeier. "Qualitätsleitsysteme für die Papierindustrie". Wochenblatt für Papierfabrikation 152, n. 6 (2024): 26–28. http://dx.doi.org/10.51202/0043-7131-2024-6-026.

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Abstract (sommario):

Tasowheel ist ein finnisches Familienunternehmen, das 1979 gegründet wurde und sich auf schlüsselfertige QLS-Projekte für Papierherstelleung und Papierverarbeitung spezialisiert hat. Das Unternehmen ist ein unabhängiger Originalhersteller mit agilen und flexiblen Abläufen, der wettbewerbsfähige Produkte anbietet. Autoren: Annely Kallioranta,Tasowheel Oy; Nicole Buschmeier, KPNB

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47

Valinluck, Boontar, Nan Sook Lee e Junichi Ryu. "A new restriction-modification system, KpnBI, recognized in Klebsiella pneumoniae". Gene 167, n. 1-2 (dicembre 1995): 59–62. http://dx.doi.org/10.1016/0378-1119(95)00660-5.

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48

van der Watt, Pauline J., Alicia Chi, Tamara Stelma, Catherine Stowell, Erin Strydom, Sarah Carden, Liselotte Angus et al. "Targeting the Nuclear Import Receptor Kpnβ1 as an Anticancer Therapeutic". Molecular Cancer Therapeutics 15, n. 4 (1 febbraio 2016): 560–73. http://dx.doi.org/10.1158/1535-7163.mct-15-0052.

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49

Nakanishi, Anna, Hiroki Okumura, Tadahiro Hashita, Aya Yamashita, Yuka Nishimura, Chihiro Watanabe, Sakina Kamimura et al. "Ivermectin Inhibits HBV Entry into the Nucleus by Suppressing KPNA2". Viruses 14, n. 11 (8 novembre 2022): 2468. http://dx.doi.org/10.3390/v14112468.

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Abstract (sommario):

Hepatitis B virus (HBV) specifically infects human hepatocytes and increases the risks of cirrhosis and liver cancer. Currently, nucleic acid analogs are the main therapeutics for chronic hepatitis caused by HBV infection. Although nucleic acid analogs can eliminate HBV DNA by inhibiting HBV reverse transcriptase, they cannot lead to negative conversion of covalently closed circular DNA (cccDNA) and hepatitis B surface antigen (HBsAg). In this study, we revealed that the antifilarial drug ivermectin suppresses HBV production by a different mechanism from the nucleic acid analog entecavir or Na+ taurocholate co-transporting polypeptide-mediated entry inhibitor cyclosporin A. Ivermectin reduced the levels of several HBV markers, including HBsAg, in HBV-infected human hepatocellular carcinoma cells (HepG2-hNTCP-C4 cells) and humanized mouse hepatocytes (PXB hepatocytes). In addition, ivermectin significantly decreased the expression of HBV core protein and the nuclear transporter karyopherin α2 (KPNA2) in the nuclei of HepG2-hNTCP-C4 cells. Furthermore, depletion of KPNA1–6 suppressed the production of cccDNA. These results suggest that KPNA1–6 is involved in the nuclear import of HBV and that ivermectin suppresses the nuclear import of HBV by inhibiting KPNA2. This study demonstrates the potential of ivermectin as a novel treatment for hepatitis B.

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50

Cohen, Yael C., Mor Zada, Shuang-Yin Wang, Ohad S. Bentur, Evgeni Chubar, Amos Cohen, Noa Lavi et al. "Single Cell RNA Sequencing in Patients Enrolled in a Selinexor Clinical Trial Reveals Overexpression of Alternative Nuclear Export Pathways Associated with Resistance to Selinexor in Refractory Multiple Myeloma". Blood 138, Supplement 1 (5 novembre 2021): 2725. http://dx.doi.org/10.1182/blood-2021-149701.

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Abstract (sommario):

Abstract Selinexor is a novel, first-in-class oral selective inhibitor of nuclear export which blocks Exportin 1 (XPO1), forcing the nuclear retention and activation of tumor suppressor proteins, ultimately causing apoptosis in cancer cells. Selinexor has been approved for the treatment of patients with penta-refractory multiple myeloma (MM) who have received at least 4 prior therapies. We previously reported the discovery of a novel transcriptional signature and therapeutic targets for therapy resistant MM by comprehensive single cell RNA-seq analysis (scRNA-seq) of plasma cells (PCs) in patients with primary refractory MM (PRMM) enrolled in the KYDAR clinical trial (NCT04065789, carfilzomib Lenalidomide dexamethasone daratumumab for PRMM [Cohen YC, Nature Med, 2021]). Here we report scRNA-seq analysis of PCs from patients with advanced refractory MM (aRRMM) (n=21) enrolled in an ancillary sub-study of a prospective clinical trial (XPORT-MM-028, NCT04414475), treated with selinexor combined with dexamethasone (Xd, in penta-refractory MM n=7), or with bortezomib, dexamethasone (XVd, in triple-class refractory [TCR] MM n=9), 5 patients participated in the ancillary study only. Median age was 75 years (range: 60-87), 50% were male, median time since active MM diagnosis was 4.8 years (range: 1.3-11.1). All treated patients (N=16) had TCR MM and 7/16 treated patients had penta-refractory MM. Single cell clustering analysis showed a unique molecular signature for each myeloma patient's PCs (Fig 1A), while patient-level analyses revealed a distinct transcriptional signature in aRRMM compared with PRMM (Fig 1B). aRRMM was characterized by upregulation of several pathways, including heparin growth factor (HDGF), Rho-GTPases activator (ARHGEF2), H3.3 histone variant and Prothymosin Alpha (PTMA) (Fig 1C-D). PPIA expression, which we previously identified as a biomarker and synergistic target for carfilzomib resistance, was low among healthy donors' PCs, progressively increased along with malignant evolution of plasma cell dyscrasia, from newly diagnosed MM, through PRMM, and was the highest in aRRMM (Fig 1C). We observed strong down-regulation of CD38 likely a consequence of daratumumab treatment and relapse in earlier lines. Finally, we discovered differential expression of several genes between patients with MM refractory to versus non-refractory (achieving at least partial response by IMWG criteria or a progression free survival greater than 4 months) to a selinexor-regimen (Fig 1E), including up-regulation of XPOT, a tRNA exportin, and KPNB1 a nucleocytoplasmic transporter (Fig 1F-G). Protein-protein interaction enrichment analyses revealed mRNA splicing and capping as well as nucleocytoplasmic transport as up-regulated modules in the refractory patients potentially serving as a resistance mechanism for blockade of XPO1 mediated nuclear export by selinexor. In summary, our study defines a roadmap for combining single cell RNA-seq profiling with clinical trials to stratify patients according to their level of anti-MM drug resistance, to define new biomarkers for drug resistance that may support personalized therapeutic decisions and reveal potential novel targets. Figure 1 Figure 1. Disclosures Cohen: Karyopharm: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; neopharm / promedico: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Bentur: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Stemer: AbbVie: Consultancy. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau. Amit: Neogene therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; CELLINK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Maruho Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck KGaA: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche Immunology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karophram: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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