Myeloid-derived suppressor cells(MDSCs)are a main driver of immunosuppression in tumors.Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new thera...Myeloid-derived suppressor cells(MDSCs)are a main driver of immunosuppression in tumors.Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new therapeutic targets to improve antitumor immunity.Here,using preclinical murine models,we discovered that exportin 1(XPO1)expression is upregulated in tumor MDSCs and that this upregulation is induced by IL-6-induced STAT3 activation during MDSC differentiation.XPO1 blockade transforms MDSCs into T-cell-activating neutrophil-like cells,enhancing the antitumor immune response and restraining tumor growth.Mechanistically,XPO1 inhibition leads to the nuclear entrapment of ERK1/2,resulting in the prevention of ERK1/2 phosphorylation following the IL-6-mediated activation of the MAPK signaling pathway.Similarly,XPO1 blockade in human MDSCs induces the formation of neutrophil-like cells with immunostimulatory functions.Therefore,our findings revealed a critical role for XPO1 in MDSC differentiation and suppressive functions;exploiting these new discoveries revealed new targets for reprogramming immunosuppressive MDSCs to improve cancer therapeutic responses.展开更多
MicroRNAs （miRNAs） are conserved small non-coding RNAs that play an important role in the regulation of gene expression and participate in a variety of biological processes. The biogenesis of miRNAs is tightly contr...MicroRNAs （miRNAs） are conserved small non-coding RNAs that play an important role in the regulation of gene expression and participate in a variety of biological processes. The biogenesis of miRNAs is tightly controlled at multiple steps, such as transcription of miRNA genes, processing by Drosha and Dicer, and transportation of precursor miRNAs （pre-miRNAs） from the nucleus to the cytoplasm by exportin-5 （XPO5）. Given the critical role of nuclear export of premiRNAs in miRNA biogenesis, any alterations of XPO5, resulting from either genetic mutation, epigenetic change, abnormal expression level or posttranslational modification, could affect miRNA expression and thus have profound effects on tumorigenesis. Importantly, XPO5 phosphorylation by ERK kinase and its cis/trans isomerization by the prolyl isomerase Pinl impair XPO5＇s nucleo-to-cytoplasmic transport ability of pre-miRNAs, leading to downregulation of mature miRNAs in hepatocellular carcinoma. In this review, we focus on how XPO5 transports pre-miRNAs in the cells and summarize the dysregnlation of XPO5 in human tumors.展开更多
The transport of proteins to and from the nucleus is necessary for many cellular processes and is one of the ways plants respond to developmental signals and environmental stresses.Nucleocytoplasmic trafficking of pro...The transport of proteins to and from the nucleus is necessary for many cellular processes and is one of the ways plants respond to developmental signals and environmental stresses.Nucleocytoplasmic trafficking of proteins is mediated by the nuclear transport receptor(NTR).Although NTR has been extensively studied in humans and Arabidopsis,it has rarely been identified and functionally characterized in rice.In this study,we identified exportin 1 in rice(OsXPO1)as a nuclear export receptor.OsXPO1shares high protein identity with its functional homologs in Arabidopsis and other organisms.OsXPO1localized to both the nucleus and the cytoplasm,directly interacted with the small GTPases OsRAN1and OsRAN2 in the nucleus,and mediated their nuclear export.Loss-of-function osxpo1 mutations were lethal at the seedling stage.Suppression of OsXPO1 expression in RNA interference lines produced multifaceted developmental defects,including arrested growth,premature senescence,abnormal inflorescence,and brown and mouth-opened spikelets.Overexpression of OsXPO1 in rice reduced plant height and seed-setting rate,but increased plant tolerance in response to PEG-mimicked drought stress and salt stress.These results indicate that OsXPO1 is a nuclear export receptor and acts in regulating plant development and abiotic stress responses.展开更多
Alterations of drug efficacy by the circadian clock are a concern when assessing drug therapies. Circadian rhythms persist in some cancer cells and are repressed in others. A better understanding of circadian activiti...Alterations of drug efficacy by the circadian clock are a concern when assessing drug therapies. Circadian rhythms persist in some cancer cells and are repressed in others. A better understanding of circadian activities generated within cancer cells could indicate therapeutic approaches that selectively disrupt rhythms and deprive cells of any benefits provided by circadian timing. Another option is to induce expression of the core clock gene Per2 to suppress cancer cell proliferation. We used the C6 rat glioblastoma cell line to identify rhythmic cancer cell properties that could provide improved therapeutic targets. Nuclear uptake of the anti-cancer agent doxorubicin by C6 cells showed a circadian rhythm that was shifted six hours from the rhythm in Per2 expression. We also observed circadian expression of the Crm1 (Xpo1) gene that is responsible for a key component of molecular transport through nuclear pores. C6 cultures include glioma stem cells (GSCs) that have elevated resistance to chemotherapeutic agents. We examined C6 tumorsphere cultures formed from GSCs to determine whether Hes1 and Bmi1 genes that maintain GSCs are under circadian clock control. Unlike Per2 gene expression in tumorspheres, Hes1 and Bmi1 expression did not oscillate in a circadian rhythm. These results highlight the importance of the nuclear pore complex in cancer treatments and suggest that the nuclear export mechanism and genes maintaining the cancer stem cell state could be inhibited therapeutically at a particular phase of the circadian cycle while preserving the tumor-suppressing abilities of Per2 gene expression.展开更多
MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) that are involved in post-transcriptional gene regulation. It has long been assumed that miRNAs exert their roles only in the cytoplasm, where they recognize their...MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) that are involved in post-transcriptional gene regulation. It has long been assumed that miRNAs exert their roles only in the cytoplasm, where they recognize their target protein-coding messenger RNAs (mRNAs), and result in translational repression or target mRNA degradation. Recent studies, however, have revealed that mature miRNAs can also be transported from the cytoplasm to the nucleus and that these nuclear miRNAs can function in an unconventional manner to regulate the biogenesis and functions of ncRNAs (including miRNAs and long ncRNAs), adding a new layer of complexity to our understanding of gene regulation. In this review, we summarize recent literature on the working model of these unconventional miRNAs and speculate on their biological significance. We have every reason to believe that these novel models of miRNA function will become a major research topic in gene regulation in eukaryotes.展开更多
基金National Institutes of Health,National Heart Lung Blood Institute(K99 HL155792,R00HL155792 to HM)Roswell Park Alliance(HM),a gift from Brendan and Elise McCarthy(PLM),and R01 CA205246(ER)+1 种基金Cytometry services were provided by the Flow and Image Cytometry Shared Resource at the Roswell Park Comprehensive Cancer Center,which is supported in part by the NCI Cancer Center Support Grant NCI R50CA211108NCI grant P30CA016056 involving the use of Roswell Park Comprehensive Cancer Center’s Genomic and Flow and Image Cytometry Shared Resources.Selinexor was provided by Karyopharm,Newton,MA.
文摘Myeloid-derived suppressor cells(MDSCs)are a main driver of immunosuppression in tumors.Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new therapeutic targets to improve antitumor immunity.Here,using preclinical murine models,we discovered that exportin 1(XPO1)expression is upregulated in tumor MDSCs and that this upregulation is induced by IL-6-induced STAT3 activation during MDSC differentiation.XPO1 blockade transforms MDSCs into T-cell-activating neutrophil-like cells,enhancing the antitumor immune response and restraining tumor growth.Mechanistically,XPO1 inhibition leads to the nuclear entrapment of ERK1/2,resulting in the prevention of ERK1/2 phosphorylation following the IL-6-mediated activation of the MAPK signaling pathway.Similarly,XPO1 blockade in human MDSCs induces the formation of neutrophil-like cells with immunostimulatory functions.Therefore,our findings revealed a critical role for XPO1 in MDSC differentiation and suppressive functions;exploiting these new discoveries revealed new targets for reprogramming immunosuppressive MDSCs to improve cancer therapeutic responses.
基金supported by the National Natural Science Foundation of China(Grant Nos.81572739 and 81772960)
文摘MicroRNAs （miRNAs） are conserved small non-coding RNAs that play an important role in the regulation of gene expression and participate in a variety of biological processes. The biogenesis of miRNAs is tightly controlled at multiple steps, such as transcription of miRNA genes, processing by Drosha and Dicer, and transportation of precursor miRNAs （pre-miRNAs） from the nucleus to the cytoplasm by exportin-5 （XPO5）. Given the critical role of nuclear export of premiRNAs in miRNA biogenesis, any alterations of XPO5, resulting from either genetic mutation, epigenetic change, abnormal expression level or posttranslational modification, could affect miRNA expression and thus have profound effects on tumorigenesis. Importantly, XPO5 phosphorylation by ERK kinase and its cis/trans isomerization by the prolyl isomerase Pinl impair XPO5＇s nucleo-to-cytoplasmic transport ability of pre-miRNAs, leading to downregulation of mature miRNAs in hepatocellular carcinoma. In this review, we focus on how XPO5 transports pre-miRNAs in the cells and summarize the dysregnlation of XPO5 in human tumors.
基金supported by the National Key Research and Development Program(2020YFA0907600)the Laboratory of Lingnan Modern Agriculture Project(NZ2021004)+1 种基金the Natural Science Foundation of Guangdong Province(2020A1515010157)the Science and Technology Program of Guangzhou(202102080499)。
文摘The transport of proteins to and from the nucleus is necessary for many cellular processes and is one of the ways plants respond to developmental signals and environmental stresses.Nucleocytoplasmic trafficking of proteins is mediated by the nuclear transport receptor(NTR).Although NTR has been extensively studied in humans and Arabidopsis,it has rarely been identified and functionally characterized in rice.In this study,we identified exportin 1 in rice(OsXPO1)as a nuclear export receptor.OsXPO1shares high protein identity with its functional homologs in Arabidopsis and other organisms.OsXPO1localized to both the nucleus and the cytoplasm,directly interacted with the small GTPases OsRAN1and OsRAN2 in the nucleus,and mediated their nuclear export.Loss-of-function osxpo1 mutations were lethal at the seedling stage.Suppression of OsXPO1 expression in RNA interference lines produced multifaceted developmental defects,including arrested growth,premature senescence,abnormal inflorescence,and brown and mouth-opened spikelets.Overexpression of OsXPO1 in rice reduced plant height and seed-setting rate,but increased plant tolerance in response to PEG-mimicked drought stress and salt stress.These results indicate that OsXPO1 is a nuclear export receptor and acts in regulating plant development and abiotic stress responses.
文摘Alterations of drug efficacy by the circadian clock are a concern when assessing drug therapies. Circadian rhythms persist in some cancer cells and are repressed in others. A better understanding of circadian activities generated within cancer cells could indicate therapeutic approaches that selectively disrupt rhythms and deprive cells of any benefits provided by circadian timing. Another option is to induce expression of the core clock gene Per2 to suppress cancer cell proliferation. We used the C6 rat glioblastoma cell line to identify rhythmic cancer cell properties that could provide improved therapeutic targets. Nuclear uptake of the anti-cancer agent doxorubicin by C6 cells showed a circadian rhythm that was shifted six hours from the rhythm in Per2 expression. We also observed circadian expression of the Crm1 (Xpo1) gene that is responsible for a key component of molecular transport through nuclear pores. C6 cultures include glioma stem cells (GSCs) that have elevated resistance to chemotherapeutic agents. We examined C6 tumorsphere cultures formed from GSCs to determine whether Hes1 and Bmi1 genes that maintain GSCs are under circadian clock control. Unlike Per2 gene expression in tumorspheres, Hes1 and Bmi1 expression did not oscillate in a circadian rhythm. These results highlight the importance of the nuclear pore complex in cancer treatments and suggest that the nuclear export mechanism and genes maintaining the cancer stem cell state could be inhibited therapeutically at a particular phase of the circadian cycle while preserving the tumor-suppressing abilities of Per2 gene expression.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.81101330,31271378,81250044 and J1103512)the Natural Science Foundation of Jiangsu Province(Nos.BK2011013 and BK2012014).
文摘MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) that are involved in post-transcriptional gene regulation. It has long been assumed that miRNAs exert their roles only in the cytoplasm, where they recognize their target protein-coding messenger RNAs (mRNAs), and result in translational repression or target mRNA degradation. Recent studies, however, have revealed that mature miRNAs can also be transported from the cytoplasm to the nucleus and that these nuclear miRNAs can function in an unconventional manner to regulate the biogenesis and functions of ncRNAs (including miRNAs and long ncRNAs), adding a new layer of complexity to our understanding of gene regulation. In this review, we summarize recent literature on the working model of these unconventional miRNAs and speculate on their biological significance. We have every reason to believe that these novel models of miRNA function will become a major research topic in gene regulation in eukaryotes.
