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Ke Shuai - One of the best experts on this subject based on the ideXlab platform.
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PIAS1 sumo ligase regulates the self renewal and differentiation of hematopoietic stem cells
The EMBO Journal, 2014Co-Authors: Bin Liu, Samuel Tahk, Kathleen M Yee, Ryan Mackie, Cary Hsu, Ke ShuaiAbstract:The selective and temporal DNA methylation plays an important role in the self-renewal and differentiation of hematopoietic stem cells (HSCs), but the molecular mechanism that controls the dynamics of DNA methylation is not understood. Here, we report that the PIAS1 epigenetic pathway plays an important role in regulating HSC self-renewal and differentiation. PIAS1 is required for maintaining the quiescence of dormant HSCs and the long-term repopulating capacity of HSC. PIAS1 disruption caused the abnormal expression of lineage-associated genes. Bisulfite sequencing analysis revealed the premature promoter demethylation of Gata1, a key myeloerythroid transcription factor and a PIAS1-target gene, in PIAS1−/− HSCs. As a result, PIAS1 disruption caused the inappropriate induction of Gata1 in HSCs and common lymphoid progenitors (CLPs). The expression of other myeloerythroid genes was also enhanced in CLPs and lineage-negative progenitors, with a concurrent repression of B cell-specific genes. Consistently, PIAS1 disruption caused enhanced myeloerythroid, but reduced B lymphoid lineage differentiation. These results identify a novel role of PIAS1 in maintaining the quiescence of dormant HSCs and in the epigenetic repression of the myeloerythroid program.
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control of specificity and magnitude of nf κb and stat1 mediated gene activation through piasy and PIAS1 cooperation
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Samuel Tahk, Bin Liu, Vasili Chernishof, Kelly A Wong, Ke ShuaiAbstract:NF-κB and STATs regulate multiple cellular processes through the transcriptional activation of genes with diversified functions. Although the molecular mechanisms that can turn on/off the overall NF-κB/STAT signaling have been extensively studied, how NF-κB/STAT-target genes can be differentially regulated is poorly understood. Here we report that PIASy, a member of the PIAS (for protein inhibitor of activated STAT) protein family, is a physiologically important transcriptional repressor of NF-κB and STAT1. Piasy deletion in dendritic cells resulted in enhanced expression of a subset of NF-κB and STAT1-dependent genes in response to LPS or IFN-γ treatment, respectively. Consistently, Piasy null mice are hypersensitive to the LPS-induced endotoxic shock. Furthermore, PIASy and PIAS1 display specific as well as redundant effects on the regulation of NF-κB/STAT1 signaling. PIAS1−/−Piasy−/− embryos died before day 11.5. The disruption of one allele of PIAS1 in the Piasy−/− background significantly enhanced the effect of Piasy deletion on the transcriptional induction of NF-κB/STAT1-dependent genes, and vice versa. Our results demonstrate that PIASy cooperates with PIAS1 to regulate the specificity and magnitude of NF-κB/STAT1-mediated gene activation.
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negative regulation of nf κb signaling by PIAS1
Molecular and Cellular Biology, 2005Co-Authors: Bin Liu, Kelly A Wong, Natalie Stein, Crescent Getman, Randy Yang, Michael A Teitell, Genhong Cheng, Ke ShuaiAbstract:The NF-B family of transcription factors is activated by a wide variety of signals to regulate a spectrum of cellular processes. The proper regulation of NF-B activity is critical, since abnormal NF-B signaling is associated with a number of human illnesses, such as chronic inflammatory diseases and cancer. We report here that PIAS1 (protein inhibitor of activated STAT1) is an important negative regulator of NF-B. Upon cytokine stimulation, the p65 subunit of NF-B translocates into the nucleus, where it interacts with PIAS1. The binding of PIAS1 to p65 inhibits cytokine-induced NF-B-dependent gene activation. PIAS1 blocks the DNA binding activity of p65 both in vitro and in vivo. Consistently, chromatin immunoprecipitation assays indicate that the binding of p65 to the promoters of NF-B-regulated genes is significantly enhanced in PIAS1/ cells. Microarray analysis indicates that the removal of PIAS1 results in an increased expression of a subset of NF-B-mediated genes in response to tumor necrosis factor alpha and lipopolysaccharide. Consistently, PIAS1 null mice showed elevated proinflammatory cytokines. Our results identify PIAS1 as a novel negative regulator of NF-B. A large variety of signals, such as proinflammatory cytokines (tumor necrosis factor alpha [TNF-] and interleukin-1 [IL-1]) and bacterial lipopolysaccharide (LPS), activate the NF-B signaling pathway. NF-B is a family of dimeric transcription
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PIAS1 selectively inhibits interferon-inducible genes and is important in innate immunity
Nature Immunology, 2004Co-Authors: Sheldon Mink, Kelly A Wong, Natalie Stein, Crescent Getman, Paul W Dempsey, Hong Wu, Ke ShuaiAbstract:Interferon (IFN) activates the signal transducer and activator of transcription (STAT) pathway to regulate immune responses. The protein inhibitor of activated STAT (PIAS) family has been suggested to negatively regulate STAT signaling. To understand the physiological function of PIAS1, we generated PIAS1 ^ −/− mice. Using PIAS1-deficient cells, we show that PIAS1 selectively regulates a subset of IFN-γ- or IFN-β-inducible genes by interfering with the recruitment of STAT1 to the gene promoter. The antiviral activity of IFN-γ or IFN-β was consistently enhanced by PIAS1 disruption. PIAS1 ^ −/− mice showed increased protection against pathogenic infection. Our data indicate that PIAS1 is a physiologically important negative regulator of STAT1 and suggest that PIAS1 is critical for the IFN-γ- or IFN-β-mediated innate immune responses.
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induction of apoptosis by protein inhibitor of activated stat1 through c jun nh2 terminal kinase activation
Journal of Biological Chemistry, 2001Co-Authors: Bin Liu, Ke ShuaiAbstract:Abstract Members of the protein inhibitor of activated signal transducer and activator of transcription (STAT) family (PIAS family) of proteins act as negative regulators of STATs in cytokine signaling. We report here that PIAS proteins have proapoptotic activity. PIAS1 induced apoptosis in both human 293T cells and human osteosarcoma U2OS cells. PIAS1 is localized in the nucleus as distinct nuclear dots. Ectopic expression of PIAS1 in U2OS cells activated JNK1 (c-Jun NH2-terminal kinase). A dominant-negative JNK1, capable of inhibiting PIAS1-induced JNK1 activation, blocked PIAS1-mediated apoptosis. Furthermore, a mutant PIAS1, lacking the first 9 amino acid residues, failed to repress Stat1-mediated gene activation although it retained its ability to activate JNK and to trigger apoptosis. Our results identify a novel function of PIAS1 in the induction of JNK-dependent apoptosis, independent of the previously known inhibitory activity of PIAS1 in STAT-mediated gene activation.
Bin Liu - One of the best experts on this subject based on the ideXlab platform.
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PIAS1 sumo ligase regulates the self renewal and differentiation of hematopoietic stem cells
The EMBO Journal, 2014Co-Authors: Bin Liu, Samuel Tahk, Kathleen M Yee, Ryan Mackie, Cary Hsu, Ke ShuaiAbstract:The selective and temporal DNA methylation plays an important role in the self-renewal and differentiation of hematopoietic stem cells (HSCs), but the molecular mechanism that controls the dynamics of DNA methylation is not understood. Here, we report that the PIAS1 epigenetic pathway plays an important role in regulating HSC self-renewal and differentiation. PIAS1 is required for maintaining the quiescence of dormant HSCs and the long-term repopulating capacity of HSC. PIAS1 disruption caused the abnormal expression of lineage-associated genes. Bisulfite sequencing analysis revealed the premature promoter demethylation of Gata1, a key myeloerythroid transcription factor and a PIAS1-target gene, in PIAS1−/− HSCs. As a result, PIAS1 disruption caused the inappropriate induction of Gata1 in HSCs and common lymphoid progenitors (CLPs). The expression of other myeloerythroid genes was also enhanced in CLPs and lineage-negative progenitors, with a concurrent repression of B cell-specific genes. Consistently, PIAS1 disruption caused enhanced myeloerythroid, but reduced B lymphoid lineage differentiation. These results identify a novel role of PIAS1 in maintaining the quiescence of dormant HSCs and in the epigenetic repression of the myeloerythroid program.
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control of specificity and magnitude of nf κb and stat1 mediated gene activation through piasy and PIAS1 cooperation
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Samuel Tahk, Bin Liu, Vasili Chernishof, Kelly A Wong, Ke ShuaiAbstract:NF-κB and STATs regulate multiple cellular processes through the transcriptional activation of genes with diversified functions. Although the molecular mechanisms that can turn on/off the overall NF-κB/STAT signaling have been extensively studied, how NF-κB/STAT-target genes can be differentially regulated is poorly understood. Here we report that PIASy, a member of the PIAS (for protein inhibitor of activated STAT) protein family, is a physiologically important transcriptional repressor of NF-κB and STAT1. Piasy deletion in dendritic cells resulted in enhanced expression of a subset of NF-κB and STAT1-dependent genes in response to LPS or IFN-γ treatment, respectively. Consistently, Piasy null mice are hypersensitive to the LPS-induced endotoxic shock. Furthermore, PIASy and PIAS1 display specific as well as redundant effects on the regulation of NF-κB/STAT1 signaling. PIAS1−/−Piasy−/− embryos died before day 11.5. The disruption of one allele of PIAS1 in the Piasy−/− background significantly enhanced the effect of Piasy deletion on the transcriptional induction of NF-κB/STAT1-dependent genes, and vice versa. Our results demonstrate that PIASy cooperates with PIAS1 to regulate the specificity and magnitude of NF-κB/STAT1-mediated gene activation.
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proinflammatory stimuli induce ikkα mediated phosphorylation of PIAS1 to restrict inflammation and immunity
Cell, 2007Co-Authors: Bin Liu, Samuel Tahk, Vasili Chernishof, Sheldon Mink, Yonghui Yang, Rachel Ogorzalek R Loo, Hyunduk Jang, Randy Yang, David B Shultz, Clifford J BelloneAbstract:Summary How inflammatory stimuli signal to the nucleus to restrict inflammation is poorly understood. Protein inhibitor of activated STAT1 (PIAS1), a transcriptional regulator that possesses small ubiquitin-related modifier (SUMO) E3 ligase activity, inhibits immune responses by selectively blocking the binding of NF-κB and STAT1 to gene promoters. We report here that PIAS1 becomes rapidly phosphorylated on Ser90 residue in response to various inflammatory stimuli. Mutational studies indicate that Ser90 phosphorylation is required for PIAS1 to repress transcription. Upon TNF treatment, wild-type PIAS1, but not the Ser90A mutant, becomes rapidly associated with the promoters of NF-κB target genes. Furthermore, IKKα, but not IKKβ, interacts with PIAS1 in vivo and mediates PIAS1 Ser90 phosphorylation, a process that requires the SUMO ligase activity of PIAS1. Our results identify a signaling pathway in which proinflammatory stimuli activate the IKKα-mediated sumoylation-dependent phosphorylation of PIAS1 for the immediate repression of inflammatory gene activation.
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negative regulation of nf κb signaling by PIAS1
Molecular and Cellular Biology, 2005Co-Authors: Bin Liu, Kelly A Wong, Natalie Stein, Crescent Getman, Randy Yang, Michael A Teitell, Genhong Cheng, Ke ShuaiAbstract:The NF-B family of transcription factors is activated by a wide variety of signals to regulate a spectrum of cellular processes. The proper regulation of NF-B activity is critical, since abnormal NF-B signaling is associated with a number of human illnesses, such as chronic inflammatory diseases and cancer. We report here that PIAS1 (protein inhibitor of activated STAT1) is an important negative regulator of NF-B. Upon cytokine stimulation, the p65 subunit of NF-B translocates into the nucleus, where it interacts with PIAS1. The binding of PIAS1 to p65 inhibits cytokine-induced NF-B-dependent gene activation. PIAS1 blocks the DNA binding activity of p65 both in vitro and in vivo. Consistently, chromatin immunoprecipitation assays indicate that the binding of p65 to the promoters of NF-B-regulated genes is significantly enhanced in PIAS1/ cells. Microarray analysis indicates that the removal of PIAS1 results in an increased expression of a subset of NF-B-mediated genes in response to tumor necrosis factor alpha and lipopolysaccharide. Consistently, PIAS1 null mice showed elevated proinflammatory cytokines. Our results identify PIAS1 as a novel negative regulator of NF-B. A large variety of signals, such as proinflammatory cytokines (tumor necrosis factor alpha [TNF-] and interleukin-1 [IL-1]) and bacterial lipopolysaccharide (LPS), activate the NF-B signaling pathway. NF-B is a family of dimeric transcription
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induction of apoptosis by protein inhibitor of activated stat1 through c jun nh2 terminal kinase activation
Journal of Biological Chemistry, 2001Co-Authors: Bin Liu, Ke ShuaiAbstract:Abstract Members of the protein inhibitor of activated signal transducer and activator of transcription (STAT) family (PIAS family) of proteins act as negative regulators of STATs in cytokine signaling. We report here that PIAS proteins have proapoptotic activity. PIAS1 induced apoptosis in both human 293T cells and human osteosarcoma U2OS cells. PIAS1 is localized in the nucleus as distinct nuclear dots. Ectopic expression of PIAS1 in U2OS cells activated JNK1 (c-Jun NH2-terminal kinase). A dominant-negative JNK1, capable of inhibiting PIAS1-induced JNK1 activation, blocked PIAS1-mediated apoptosis. Furthermore, a mutant PIAS1, lacking the first 9 amino acid residues, failed to repress Stat1-mediated gene activation although it retained its ability to activate JNK and to trigger apoptosis. Our results identify a novel function of PIAS1 in the induction of JNK-dependent apoptosis, independent of the previously known inhibitory activity of PIAS1 in STAT-mediated gene activation.
Masahide Takahashi - One of the best experts on this subject based on the ideXlab platform.
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pias proteins are involved in the sumo 1 modification intracellular translocation and transcriptional repressive activity of ret finger protein
Experimental Cell Research, 2005Co-Authors: Tetsuo Matsuura, Yohei Shimono, Kumi Kawai, Hideki Murakami, Takeshi Urano, Yasumasa Niwa, Hidemi Goto, Masahide TakahashiAbstract:Abstract Ret finger protein (RFP) is a nuclear protein that is highly expressed in testis and in various tumor cell lines. RFP functions as a transcriptional repressor and associates with Enhancer of Polycomb 1 (EPC1), a member of the Polycomb group proteins, and Mi-2β, a main component of the nucleosome remodeling and deacetylase (NuRD) complex. We show that RFP binds with PIAS (protein inhibitor of activated STAT) proteins, PIAS1, PIAS3, PIASxα and PIASy at their carboxyl-terminal region and is covalently modified by SUMO-1 (sumoylation). PIAS proteins enhance the sumoylation of RFP in a dose-dependent manner and induce the translocation of RFP into nuclear bodies reminiscent of the PML bodies. In addition, co-expression of PIAS proteins or SUMO-1 strengthened the transcriptional repressive activity of RFP. Finally, our immunohistochemical results show that RFP, SUMO-1 and PIASy localize in a characteristic nuclear structure juxtaposed with the inner nuclear membrane (XY body) of primary spermatocytes in mouse testis. These results demonstrate that the intracellular location and the transcriptional activity of RFP are modified by PIAS proteins which possess SUMO E3 ligase activities and suggest that they may play a co-operative role in spermatogenesis.
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pias proteins are involved in the sumo 1 modification intracellular translocation and transcriptional repressive activity of ret finger protein
Experimental Cell Research, 2005Co-Authors: Tetsuo Matsuura, Yohei Shimono, Kumi Kawai, Hideki Murakami, Takeshi Urano, Yasumasa Niwa, Hidemi Goto, Masahide TakahashiAbstract:Ret finger protein (RFP) is a nuclear protein that is highly expressed in testis and in various tumor cell lines. RFP functions as a transcriptional repressor and associates with Enhancer of Polycomb 1 (EPC1), a member of the Polycomb group proteins, and Mi-2beta, a main component of the nucleosome remodeling and deacetylase (NuRD) complex. We show that RFP binds with PIAS (protein inhibitor of activated STAT) proteins, PIAS1, PIAS3, PIASxalpha and PIASy at their carboxyl-terminal region and is covalently modified by SUMO-1 (sumoylation). PIAS proteins enhance the sumoylation of RFP in a dose-dependent manner and induce the translocation of RFP into nuclear bodies reminiscent of the PML bodies. In addition, co-expression of PIAS proteins or SUMO-1 strengthened the transcriptional repressive activity of RFP. Finally, our immunohistochemical results show that RFP, SUMO-1 and PIASy localize in a characteristic nuclear structure juxtaposed with the inner nuclear membrane (XY body) of primary spermatocytes in mouse testis. These results demonstrate that the intracellular location and the transcriptional activity of RFP are modified by PIAS proteins which possess SUMO E3 ligase activities and suggest that they may play a co-operative role in spermatogenesis.
Wolfgang Wurst - One of the best experts on this subject based on the ideXlab platform.
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disruption of the murine piasx gene results in reduced testis weight
Journal of Molecular Endocrinology, 2005Co-Authors: Henrikki Santti, Laura Mikkonen, Sirpa J Hirvonensantti, F Vauti, M Perera, Ashish Anand, Markus Panhuysen, Giorgio Corte, Jorma Toppari, Wolfgang WurstAbstract:PIASx belongs to the PIAS protein family, the members of which modulate activities of several transcription factors and act as E3 ligases in the sumoylation pathway. The PIASx gene is highly expressed in testis, suggesting a role in spermatogenesis. To investigate the function of PIASx in vivo, we have disrupted the PIASx gene in mice. Interestingly, the knockout mice were viable and fertile. Despite the normal fertility, the testis weight of the mutant animals was reduced and their number of apoptotic testicular cells was increased. Also, the sperm count of mutant mice tended to be reduced, but the quality of their sperm cells was normal. No significant changes were observed in the serum levels of LH and FSH or in the intratesticular testosterone concentration between the knockout animals and their wild-type littermates. Compensatory increases in other PIAS protein mRNAs were not observed in the knockout mice. These results imply that PIASx is required quantitatively rather than qualitatively for normal spermatogenesis.
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disruption of the murine piasx gene results in reduced testis weight
Journal of Molecular Endocrinology, 2005Co-Authors: Henrikki Santti, Laura Mikkonen, Sirpa J Hirvonensantti, F Vauti, M Perera, Ashish Anand, Markus Panhuysen, Giorgio Corte, Jorma Toppari, Wolfgang WurstAbstract:PIASx belongs to the PIAS protein family, the members of which modulate activities of several transcription factors and act as E3 ligases in the sumoylation pathway. The PIASx gene is highly expressed in testis, suggesting a role in spermatogenesis. To investigate the function of PIASx in vivo, we have disrupted the PIASx gene in mice. Interestingly, the knockout mice were viable and fertile. Despite the normal fertility, the testis weight of the mutant animals was reduced and their number of apoptotic testicular cells was increased. Also, the sperm count of mutant mice tended to be reduced, but the quality of their sperm cells was normal. No significant changes were observed in the serum levels of LH and FSH or in the intratesticular testosterone concentration between the knockout animals and their wild-type littermates. Compensatory increases in other PIAS protein mRNAs were not observed in the knockout mice. These results imply that PIASx is required quantitatively rather than qualitatively for normal spermatogenesis.
Tetsuo Matsuura - One of the best experts on this subject based on the ideXlab platform.
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pias proteins are involved in the sumo 1 modification intracellular translocation and transcriptional repressive activity of ret finger protein
Experimental Cell Research, 2005Co-Authors: Tetsuo Matsuura, Yohei Shimono, Kumi Kawai, Hideki Murakami, Takeshi Urano, Yasumasa Niwa, Hidemi Goto, Masahide TakahashiAbstract:Abstract Ret finger protein (RFP) is a nuclear protein that is highly expressed in testis and in various tumor cell lines. RFP functions as a transcriptional repressor and associates with Enhancer of Polycomb 1 (EPC1), a member of the Polycomb group proteins, and Mi-2β, a main component of the nucleosome remodeling and deacetylase (NuRD) complex. We show that RFP binds with PIAS (protein inhibitor of activated STAT) proteins, PIAS1, PIAS3, PIASxα and PIASy at their carboxyl-terminal region and is covalently modified by SUMO-1 (sumoylation). PIAS proteins enhance the sumoylation of RFP in a dose-dependent manner and induce the translocation of RFP into nuclear bodies reminiscent of the PML bodies. In addition, co-expression of PIAS proteins or SUMO-1 strengthened the transcriptional repressive activity of RFP. Finally, our immunohistochemical results show that RFP, SUMO-1 and PIASy localize in a characteristic nuclear structure juxtaposed with the inner nuclear membrane (XY body) of primary spermatocytes in mouse testis. These results demonstrate that the intracellular location and the transcriptional activity of RFP are modified by PIAS proteins which possess SUMO E3 ligase activities and suggest that they may play a co-operative role in spermatogenesis.
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pias proteins are involved in the sumo 1 modification intracellular translocation and transcriptional repressive activity of ret finger protein
Experimental Cell Research, 2005Co-Authors: Tetsuo Matsuura, Yohei Shimono, Kumi Kawai, Hideki Murakami, Takeshi Urano, Yasumasa Niwa, Hidemi Goto, Masahide TakahashiAbstract:Ret finger protein (RFP) is a nuclear protein that is highly expressed in testis and in various tumor cell lines. RFP functions as a transcriptional repressor and associates with Enhancer of Polycomb 1 (EPC1), a member of the Polycomb group proteins, and Mi-2beta, a main component of the nucleosome remodeling and deacetylase (NuRD) complex. We show that RFP binds with PIAS (protein inhibitor of activated STAT) proteins, PIAS1, PIAS3, PIASxalpha and PIASy at their carboxyl-terminal region and is covalently modified by SUMO-1 (sumoylation). PIAS proteins enhance the sumoylation of RFP in a dose-dependent manner and induce the translocation of RFP into nuclear bodies reminiscent of the PML bodies. In addition, co-expression of PIAS proteins or SUMO-1 strengthened the transcriptional repressive activity of RFP. Finally, our immunohistochemical results show that RFP, SUMO-1 and PIASy localize in a characteristic nuclear structure juxtaposed with the inner nuclear membrane (XY body) of primary spermatocytes in mouse testis. These results demonstrate that the intracellular location and the transcriptional activity of RFP are modified by PIAS proteins which possess SUMO E3 ligase activities and suggest that they may play a co-operative role in spermatogenesis.