The Experts below are selected from a list of 33294 Experts worldwide ranked by ideXlab platform
Veronica Rodriguezbravo - One of the best experts on this subject based on the ideXlab platform.
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nuclear pores promote lethal prostate cancer by increasing POM121 driven e2f1 myc and ar nuclear import
Cell, 2018Co-Authors: Veronica Rodriguezbravo, Raffaella Pippa, Wonmin Song, Marc Carcelescordon, Ana Dominguezandres, Naoto FujiwaraAbstract:Summary Nuclear pore complexes (NPCs) regulate nuclear-cytoplasmic transport, transcription, and genome integrity in eukaryotic cells. However, their functional roles in cancer remain poorly understood. We interrogated the evolutionary transcriptomic landscape of NPC components, nucleoporins (Nups), from primary to advanced metastatic human prostate cancer (PC). Focused loss-of-function genetic screen of top-upregulated Nups in aggressive PC models identified POM121 as a key contributor to PC aggressiveness. Mechanistically, POM121 promoted PC progression by enhancing importin-dependent nuclear transport of key oncogenic (E2F1, MYC) and PC-specific (AR-GATA2) transcription factors, uncovering a pharmacologically targetable axis that, when inhibited, decreased tumor growth, restored standard therapy efficacy, and improved survival in patient-derived pre-clinical models. Our studies molecularly establish a role of NPCs in PC progression and give a rationale for NPC-regulated nuclear import targeting as a therapeutic strategy for lethal PC. These findings may have implications for understanding how NPC deregulation contributes to the pathogenesis of other tumor types.
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nuclear pores promote lethal prostate cancer by increasing POM121 driven e2f1 myc and ar nuclear import
Cell, 2018Co-Authors: Veronica Rodriguezbravo, Raffaella Pippa, Wonmin Song, Marc Carcelescordon, Ana Dominguezandres, Naoto FujiwaraAbstract:Nuclear pore complexes (NPCs) regulate nuclear-cytoplasmic transport, transcription, and genome integrity in eukaryotic cells. However, their functional roles in cancer remain poorly understood. We interrogated the evolutionary transcriptomic landscape of NPC components, nucleoporins (Nups), from primary to advanced metastatic human prostate cancer (PC). Focused loss-of-function genetic screen of top-upregulated Nups in aggressive PC models identified POM121 as a key contributor to PC aggressiveness. Mechanistically, POM121 promoted PC progression by enhancing importin-dependent nuclear transport of key oncogenic (E2F1, MYC) and PC-specific (AR-GATA2) transcription factors, uncovering a pharmacologically targetable axis that, when inhibited, decreased tumor growth, restored standard therapy efficacy, and improved survival in patient-derived pre-clinical models. Our studies molecularly establish a role of NPCs in PC progression and give a rationale for NPC-regulated nuclear import targeting as a therapeutic strategy for lethal PC. These findings may have implications for understanding how NPC deregulation contributes to the pathogenesis of other tumor types.
Einar Hallberg - One of the best experts on this subject based on the ideXlab platform.
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er retention may play a role in sorting of the nuclear pore membrane protein POM121 towards the npc
2016Co-Authors: Gabriela Imreh, Jacques Boutet De Monvel, Laura Branden, Einar HallbergAbstract:ER retention may play a role in sorting of the nuclear pore membrane Protein POM121 towards the NPC
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degradation of gfp labelled POM121 a non invasive sensor of nuclear apoptosis precedes clustering of nuclear pores and externalisation of phosphatidylserine
Apoptosis, 2004Co-Authors: Marie Beckman, Madeleine Kihlmark, Kerstin Iverfeldt, Einar HallbergAbstract:The nuclear pore membrane protein POM121 is specifically degraded during apoptosis by a caspase-3-dependent process enabling early detection of apoptosis in living cells expressing POM121-GFP. Here we further investigated temporal aspects of apoptotic degradation of POM121-GFP. We demonstrate that decreased POM121-GFP fluorescence precedes annexin V-labelling of apoptotic cells. This indicates that degradation of the nuclear pore complex starts prior to redistribution of plasma membrane phosphatidylserine, which serves as a signal for phagocytotic elimination of apoptotic cells. Furthermore, a caspase-resistant GFP-labelled mutant of POM121 resisted degradation even in late apoptosis and was detected in clustered nuclear pores. Thus, it can be concluded that loss of POM121-GFP is a specific sensor of the activation of caspase-3-dependent proteolysis at the nuclear pores.
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er retention may play a role in sorting of the nuclear pore membrane protein POM121
Experimental Cell Research, 2003Co-Authors: Gabriela Imreh, Jacques Boutet De Monvel, Laura Branden, Danuta Maksel, Einar HallbergAbstract:Integral membrane proteins of the nuclear envelope (NE) are synthesized on the rough endoplasmic reticulum (ER) and following free diffusion in the continuous ER/NE membrane system are targeted to ...
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formation of nuclear bodies in cells overexpressing the nuclear pore protein POM121
Experimental Cell Research, 1996Co-Authors: Henrik Soderqvist, Weiqin Jiang, N R Ringertz, Einar HallbergAbstract:POM121 is an integral membrane protein specifically localized in the pore membrane domain of the nuclear envelope. We have investigated the intracellular distribution of rat POM121 heterologously overexpressed in monkey COS cells by immunofluorescence and fluorescence digital imaging microscopy. At low levels of expression overexpressed POM121 was distributed in the nuclear envelope in a punctate fashion, partially overlapping with the distribution of nuclear pores. At high levels of expression, however, the overexpressed protein accumulated in intranuclear bodies. These bodies represent a novel subnuclear structure, displaying a defined cylindrical structure and a distinct localization at or adjacent to the inner nuclear membrane. The C-terminal portion of POM121, which contains a pentapeptide repeat domain common to a subfamily of related nucleoporins, was sufficient to mediate targeting to the nuclear envelope as well as formation of intranuclear bodies.
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the large c terminal region of the integral pore membrane protein POM121 is facing the nuclear pore complex
European Journal of Cell Biology, 1994Co-Authors: Henrik Soderqvist, Einar HallbergAbstract:POM121 is an integral membrane protein that has been specifically localized to the "pore membrane" domain of the nuclear envelope. Based on its cDNA-deduced primary structure it was suggested that POM121 contains one or two transmembrane segments and that its major C-terminal portion faces the pore side rather than the cisternal side of the pore membrane. We have investigated the membrane topology of POM121 by studying the accessibility of a C-terminal and an N-terminal epitope of POM121 for epitope-specific antibodies. The accessibility of POM121 in unfixed, semi-intact or permeabilized tissue culture cells was analyzed by indirect immunofluorescence. We found that the C-terminal epitope was accessible for antibodies in both semi-intact and permeabilized cells, whereas the N-terminal epitope was only accessible in the permeabilized cells. The results show that the large C-terminal region of POM121, containing more than 90% of its total mass, is exposed on the pore side of the nuclear membrane and suggest that the N-terminal portion is most likely localized in the perinuclear space. The data also show that at least part of the C-terminal epitopes are localized on the cytoplasmic side of the nuclear envelope. The topology suggests that the C-terminal portion of POM121, which contains a nucleoporin-like domain, interacts with the nuclear pore complex and thus, may play a role in biogenesis of the nuclear envelope and the nuclear pore complex.
Tokuko Haraguchi - One of the best experts on this subject based on the ideXlab platform.
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newly found tetrahymena nucleoporins nup214 nup153 and POM121 pom82 differentiate nuclear pore complexes of functionally distinct nuclei
Communicative & Integrative Biology, 2018Co-Authors: Masaaki Iwamoto, Yasushi Hiraoka, Tokuko HaraguchiAbstract:The nuclear pore complex (NPC) is the sole gateway for molecular transport between the nucleus and the cytoplasm in eukaryotes. The NPC is composed of approximately 30 different kinds of protein co...
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Compositionally distinct nuclear pore complexes of functionally distinct dimorphic nuclei in the ciliate Tetrahymena.
Journal of Cell Science, 2017Co-Authors: Masaaki Iwamoto, Hiroko Osakada, Chie Mori, Yasuhiro Fukuda, Yasushi Hiraoka, Koji Nagao, Chikashi Obuse, Tokuko HaraguchiAbstract:ABSTRACT The nuclear pore complex (NPC), a gateway for nucleocytoplasmic trafficking, is composed of ∼30 different proteins called nucleoporins. It remains unknown whether the NPCs within a species are homogeneous or vary depending on the cell type or physiological condition. Here, we present evidence for compositionally distinct NPCs that form within a single cell in a binucleated ciliate. In Tetrahymena thermophila , each cell contains both a transcriptionally active macronucleus (MAC) and a germline micronucleus (MIC). By combining in silico analysis, mass spectrometry analysis for immuno-isolated proteins and subcellular localization analysis of GFP-fused proteins, we identified numerous novel components of MAC and MIC NPCs. Core members of the Nup107–Nup160 scaffold complex were enriched in MIC NPCs. Strikingly, two paralogs of Nup214 and of Nup153 localized exclusively to either the MAC or MIC NPCs. Furthermore, the transmembrane components POM121 and Pom82 localize exclusively to MAC and MIC NPCs, respectively. Our results argue that functional nuclear dimorphism in ciliates is likely to depend on the compositional and structural specificity of NPCs.
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Compositionally distinct nuclear pore complexes of functionally distinct dimorphic nuclei in ciliate Tetrahymena
bioRxiv, 2017Co-Authors: Masaaki Iwamoto, Hiroko Osakada, Chie Mori, Yasuhiro Fukuda, Yasushi Hiraoka, Koji Nagao, Chikashi Obuse, Tokuko HaraguchiAbstract:The nuclear pore complex (NPC), a gateway for nucleocytoplasmic trafficking, is composed of about 30 different proteins called nucleoporins. It remains unknown whether the NPCs within a species are homogeneous or vary depending on the cell type, or physiological condition. Here, we present evidence for compositionally distinct NPCs that form within a single cell in a binucleated ciliate. In Tetrahymena thermophila, each cell contains both a transcriptionally-active macronucleus (MAC) and a germline micronucleus (MIC). By combining in silico analysis, mass spectrometry analysis for immuno-isolated proteins, and subcellular localization analysis of GFP fused proteins, we identified numerous novel components of MAC and MIC NPCs. Core members of the Nup107-160 scaffold complex were enriched in MIC NPCs. Strikingly, two paralogs of Nup214 and of Nup153 localized exclusively to either MAC or MIC NPCs. Furthermore, the transmembrane components POM121 and Pom82 localize exclusively to MAC and MIC NPCs, respectively. Our results argue that functional nuclear dimorphism in ciliates is likely to depend on compositional and structural specificity of NPCs.
Naoto Fujiwara - One of the best experts on this subject based on the ideXlab platform.
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nuclear pores promote lethal prostate cancer by increasing POM121 driven e2f1 myc and ar nuclear import
Cell, 2018Co-Authors: Veronica Rodriguezbravo, Raffaella Pippa, Wonmin Song, Marc Carcelescordon, Ana Dominguezandres, Naoto FujiwaraAbstract:Summary Nuclear pore complexes (NPCs) regulate nuclear-cytoplasmic transport, transcription, and genome integrity in eukaryotic cells. However, their functional roles in cancer remain poorly understood. We interrogated the evolutionary transcriptomic landscape of NPC components, nucleoporins (Nups), from primary to advanced metastatic human prostate cancer (PC). Focused loss-of-function genetic screen of top-upregulated Nups in aggressive PC models identified POM121 as a key contributor to PC aggressiveness. Mechanistically, POM121 promoted PC progression by enhancing importin-dependent nuclear transport of key oncogenic (E2F1, MYC) and PC-specific (AR-GATA2) transcription factors, uncovering a pharmacologically targetable axis that, when inhibited, decreased tumor growth, restored standard therapy efficacy, and improved survival in patient-derived pre-clinical models. Our studies molecularly establish a role of NPCs in PC progression and give a rationale for NPC-regulated nuclear import targeting as a therapeutic strategy for lethal PC. These findings may have implications for understanding how NPC deregulation contributes to the pathogenesis of other tumor types.
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nuclear pores promote lethal prostate cancer by increasing POM121 driven e2f1 myc and ar nuclear import
Cell, 2018Co-Authors: Veronica Rodriguezbravo, Raffaella Pippa, Wonmin Song, Marc Carcelescordon, Ana Dominguezandres, Naoto FujiwaraAbstract:Nuclear pore complexes (NPCs) regulate nuclear-cytoplasmic transport, transcription, and genome integrity in eukaryotic cells. However, their functional roles in cancer remain poorly understood. We interrogated the evolutionary transcriptomic landscape of NPC components, nucleoporins (Nups), from primary to advanced metastatic human prostate cancer (PC). Focused loss-of-function genetic screen of top-upregulated Nups in aggressive PC models identified POM121 as a key contributor to PC aggressiveness. Mechanistically, POM121 promoted PC progression by enhancing importin-dependent nuclear transport of key oncogenic (E2F1, MYC) and PC-specific (AR-GATA2) transcription factors, uncovering a pharmacologically targetable axis that, when inhibited, decreased tumor growth, restored standard therapy efficacy, and improved survival in patient-derived pre-clinical models. Our studies molecularly establish a role of NPCs in PC progression and give a rationale for NPC-regulated nuclear import targeting as a therapeutic strategy for lethal PC. These findings may have implications for understanding how NPC deregulation contributes to the pathogenesis of other tumor types.
Ana Dominguezandres - One of the best experts on this subject based on the ideXlab platform.
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nuclear pores promote lethal prostate cancer by increasing POM121 driven e2f1 myc and ar nuclear import
Cell, 2018Co-Authors: Veronica Rodriguezbravo, Raffaella Pippa, Wonmin Song, Marc Carcelescordon, Ana Dominguezandres, Naoto FujiwaraAbstract:Summary Nuclear pore complexes (NPCs) regulate nuclear-cytoplasmic transport, transcription, and genome integrity in eukaryotic cells. However, their functional roles in cancer remain poorly understood. We interrogated the evolutionary transcriptomic landscape of NPC components, nucleoporins (Nups), from primary to advanced metastatic human prostate cancer (PC). Focused loss-of-function genetic screen of top-upregulated Nups in aggressive PC models identified POM121 as a key contributor to PC aggressiveness. Mechanistically, POM121 promoted PC progression by enhancing importin-dependent nuclear transport of key oncogenic (E2F1, MYC) and PC-specific (AR-GATA2) transcription factors, uncovering a pharmacologically targetable axis that, when inhibited, decreased tumor growth, restored standard therapy efficacy, and improved survival in patient-derived pre-clinical models. Our studies molecularly establish a role of NPCs in PC progression and give a rationale for NPC-regulated nuclear import targeting as a therapeutic strategy for lethal PC. These findings may have implications for understanding how NPC deregulation contributes to the pathogenesis of other tumor types.
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nuclear pores promote lethal prostate cancer by increasing POM121 driven e2f1 myc and ar nuclear import
Cell, 2018Co-Authors: Veronica Rodriguezbravo, Raffaella Pippa, Wonmin Song, Marc Carcelescordon, Ana Dominguezandres, Naoto FujiwaraAbstract:Nuclear pore complexes (NPCs) regulate nuclear-cytoplasmic transport, transcription, and genome integrity in eukaryotic cells. However, their functional roles in cancer remain poorly understood. We interrogated the evolutionary transcriptomic landscape of NPC components, nucleoporins (Nups), from primary to advanced metastatic human prostate cancer (PC). Focused loss-of-function genetic screen of top-upregulated Nups in aggressive PC models identified POM121 as a key contributor to PC aggressiveness. Mechanistically, POM121 promoted PC progression by enhancing importin-dependent nuclear transport of key oncogenic (E2F1, MYC) and PC-specific (AR-GATA2) transcription factors, uncovering a pharmacologically targetable axis that, when inhibited, decreased tumor growth, restored standard therapy efficacy, and improved survival in patient-derived pre-clinical models. Our studies molecularly establish a role of NPCs in PC progression and give a rationale for NPC-regulated nuclear import targeting as a therapeutic strategy for lethal PC. These findings may have implications for understanding how NPC deregulation contributes to the pathogenesis of other tumor types.