Ran GTPase-Activating Protein 1 Is a Therapeutic Target in Diffuse Large B-Cell Lymphoma

Chang, Kung Chao; Chang, Wei Chao; Chang, Yao; Hung, Liang‐Yi; Lai, Chin‐Feng; Yeh, Yu Min; Chou, Yu Wei; Chen, Chung Hsuan

doi:10.1371/journal.pone.0079863

Cited by 14 publications

(14 citation statements)

References 50 publications

(60 reference statements)

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“…Consistent with this, four key nuclear transport factors, including CRM1, RanGAP1, Ran and RanBP1, are overexpressed in metastatic melanomas compared to primary melanomas and melanocytic nevi [ 63 ]. Further, RanGAP1 has been found as a potential marker and therapeutic target for aggressive B-cell lymphoma, especially diffuse large B-cell lymphoma (DLBCL) [ 73 ]. Because the primarily localization of RanGAP1 in the cytoplasm and at the NPC is required for efficient nuclear transport especially in cancer cells, targeting CRM1 with small-molecule inhibitors in certain types of cancers with overexpression of RanGAP1 and/or CRM1 might be a promising strategy for therapeutic treatment of these diseases.…”

Section: Discussionmentioning

confidence: 99%

The Cellular Distribution of RanGAP1 Is Regulated by CRM1-Mediated Nuclear Export in Mammalian Cells

et al. 2015

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The Ran GTPase activating protein RanGAP1 plays an essential role in nuclear transport by stimulating RanGTP hydrolysis in the cytoplasmic compartment. In mammalian cells, unmodified RanGAP1 is predominantly cytoplasmic, whereas modification by small ubiquitin-related modifier protein (SUMO) targets RanGAP1 to the cytoplasmic filaments of nuclear pore complex (NPC). Although RanGAP1 contains nine putative nuclear export signals and a nuclear localization signal, little is known if RanGAP1 shuttles between the nuclear and cytoplasmic compartments and how its primary localization in the cytoplasm and at the NPC is regulated. Here we show that inhibition of CRM1-mediated nuclear export using RNAi-knockdown of CRM1 and inactivation of CRM1 by leptomycin B (LMB) results in nuclear accumulation of RanGAP1. LMB treatment induced a more robust redistribution of RanGAP1 from the cytoplasm to the nucleoplasm compared to CRM1 RNAi and also uniquely triggered a decrease or loss of RanGAP1 localization at the NPC, suggesting that LMB treatment is more effective in inhibiting CRM1-mediated nuclear export of RanGAP1. Our time-course analysis of LMB treatment reveals that the NPC-associated RanGAP1 is much more slowly redistributed to the nucleoplasm than the cytoplasmic RanGAP1. Furthermore, LMB-induced nuclear accumulation of RanGAP1 is positively correlated with an increase in levels of SUMO-modified RanGAP1, suggesting that SUMOylation of RanGAP1 may mainly take place in the nucleoplasm. Lastly, we demonstrate that the nuclear localization signal at the C-terminus of RanGAP1 is required for its nuclear accumulation in cells treated with LMB. Taken together, our results elucidate that RanGAP1 is actively transported between the nuclear and cytoplasmic compartments, and that the cytoplasmic and NPC localization of RanGAP1 is dependent on CRM1-mediated nuclear export.

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Section: Discussionmentioning

confidence: 99%

The Cellular Distribution of RanGAP1 Is Regulated by CRM1-Mediated Nuclear Export in Mammalian Cells

et al. 2015

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“…OCI-Ly3 and U2932 cells (originally purchased from Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ), Germany) were gifts from Dr. Chun-Yu Liu (Taipei Veterans General Hospital, Taiwan). SU-DHL-5 and HT cell lines were obtained from Dr. Kung-Chao Chang (National Cheng Kung University, Taiwan) and have been described previously 45 . The OEC-M1 human head and neck cancer cell line was provided by Dr. Kuo-Wei Chang (National Yang-Ming University of Taiwan).…”

Section: Methodsmentioning

confidence: 99%

STAT3-coordinated migration facilitates the dissemination of diffuse large B-cell lymphomas

et al. 2018

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The motile characteristics and mechanisms that drive the dissemination of diffuse large B-cell lymphoma (DLBCL) are elusive. Here, we show that DLBCL initiates dissemination through activating STAT3-mediated amoeboid migration. Mechanistically, STAT3 activates RHOH transcription, which competes with the RhoGDP dissociation inhibitor RhoGDIγ to activate RhoA. In addition, activated STAT3 regulates microtubule dynamics and releases ARHGEF2 to activate RhoA. Both the JAK inhibitor ruxolitinib and the microtubule stabilizer Taxol suppress DLBCL cell dissemination in vivo. A clinical DLBCL sample analysis shows that STAT3-driven amoeboid movement is particularly important for the transition from stage I to stage II. This study elucidates the mechanism of DLBCL dissemination and progression and highlights the potential of combating advanced DLBCL with a JAK/STAT inhibitor or microtubule stabilizer to reduce DLBCL motility; these findings may have a great impact on the development of patient-tailored treatments for DLBCL.

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“…We found that RNAi-mediated RanGAP reduction induces cell cycle arrest of undifferentiated CPCs, where endogenous Cdc6 is localized to the cytoplasm. It has previously been reported that RNAimediated down-regulation of RanGAP expression induces cell cycle arrest in human coronary artery smooth muscle cells and B-cell lymphoma cells (Chang et al 2013;Vorpahl et al 2014). Thus, we assume that forced reduction in RanGAP levels in proliferative cells induces cell cycle arrest, at least in part, due to impeded nuclear import of Cdc6.…”

Section: Discussionmentioning

confidence: 84%

“…It has previously been reported that RNAi‐mediated down‐regulation of RanGAP expression induces cell cycle arrest in human coronary artery smooth muscle cells and B‐cell lymphoma cells (Chang et al . ; Vorpahl et al . ).…”

Section: Discussionmentioning

confidence: 99%

Terminal differentiation of cortical neurons rapidly remodels RanGAP‐mediated nuclear transport system

et al. 2016

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Terminal differentiation of neurons is accompanied by irreversible exit from the cell cycle and expression of neuronal phenotypes. The molecular mechanism whereby committed neuronal progenitors lose their ability to reenter the cell cycle is largely unknown. Here, we report that the nuclear transport system is rapidly remodeled in primary cortical progenitor cells (CPCs) at the very beginning of neuronal terminal differentiation. High levels of Ran GTPase‐activating protein 1 (RanGAP), a key regulator of the Ran GTP‐GDP cycle, in primary CPCs are drastically reduced upon neuronal induction. Small ubiquitin‐like modifier (SUMO)‐2/3‐conjugated RanGAP undergoes desumoylation and degradation in neuronally committed CPCs, where reduced RanGAP levels impede the nuclear import of nucleocytoplasmic shuttling proteins including the DNA replication initiation factor Cdc6. Furthermore, RNAi‐mediated down‐regulation of RanGAP expression in undifferentiated CPCs induces neuronal phenotypes including cell cycle exit. Our data suggest that remodeling of the RanGAP‐mediated nuclear transport system plays a key role in cell cycle exit for terminal differentiation of cortical neurons.

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Ran GTPase-Activating Protein 1 Is a Therapeutic Target in Diffuse Large B-Cell Lymphoma

Cited by 14 publications

References 50 publications

The Cellular Distribution of RanGAP1 Is Regulated by CRM1-Mediated Nuclear Export in Mammalian Cells

The Cellular Distribution of RanGAP1 Is Regulated by CRM1-Mediated Nuclear Export in Mammalian Cells

STAT3-coordinated migration facilitates the dissemination of diffuse large B-cell lymphomas

Terminal differentiation of cortical neurons rapidly remodels RanGAP‐mediated nuclear transport system

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