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Dianne Robert Soprano - One of the best experts on this subject based on the ideXlab platform.
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Role of Acinus in regulating retinoic acid-responsive gene pre-mRNA splicing.
Journal of cellular physiology, 2014Co-Authors: Fang Wang, Kenneth J. Soprano, Dianne Robert SopranoAbstract:Acinus-S’ is a corepressor for retinoic acid receptor (RAR)-dependent gene transcription and has been suggested to be involved in RNA processing. In this study, the role of Acinus isoforms in regulating pre-mRNA splicing was explored using in vivo splicing assays. Both Acinus-L and Acinus-S’, with the activity of Acinus-L higher than that of Acinus-S’, increase the splicing of a retinoic acid (RA)-responsive minigene containing a weak 5′ splice site but not a RA-responsive minigene containing a strong 5′ splice site. RA treatment further enhances the splicing of the weak 5′ splice site by Acinus in a dose- and time-dependent manner, suggesting a RA-dependent activity in addition to a RA-independent activity of Acinus. The RA-independent effect of Acinus occurs to varying degrees using minigene constructs containing several different promoters, while the RA-dependent splicing activity of Acinus is specific for transcripts derived from the minigene driven by a RA response element (RARE)-containing promoter. This suggests that the ligand-dependent splicing activity of Acinus is related to the RA-activated RAR bound to the RARE. The RRM domain is necessary for the RA-dependent splicing activity of Acinus and the RA-independent splicing activity of Acinus is repressed by RNPS1. Importantly, measurement of the splicing of endogenous human RARβ and Bcl-x in vivo demonstrates that Acinus stimulates the use of the weaker alternative 5′ splice site of these two genes in a RA-dependent manner for RARβ and a RA-independent manner for Bcl-x. Taken together, these studies demonstrate that Acinus functions in both RAR-dependent splicing and RAR-dependent transcription. J. Cell. Physiol. 230: 791–801, 2015. © 2014 Wiley Periodicals, Inc.
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the sap motif and c terminal rs and rd e rich region influences the sub nuclear localization of Acinus isoforms
Journal of Cellular Biochemistry, 2014Co-Authors: Fang Wang, Karen S. Wendling, Kenneth J. Soprano, Dianne Robert SopranoAbstract:Acinus has been reported to function in apoptosis, RNA processing and regulation of gene transcription including RA-dependent transcription. There are three different isoforms of Acinus termed Acinus-L, Acinus-S′ and Acinus-S. The isoforms of Acinus differ in their N-terminus while the C-terminus is consistent in all isoforms. The sub-nuclear localization of Acinus-L and Acinus-S′ was determined using fluorescence microscopy. Acinus-S′ colocalizes with SC35 in nuclear speckles while Acinus-L localizes diffusely throughout the nucleoplasm. RA treatment has little effect on the sub-nuclear localization of Acinus-L and Acinus-S′. The domains/regions necessary for the distinct sub-nuclear localization of Acinus-L and Acinus-S′ were identified. The speckled sub-nuclear localization of Acinus-S′ is dependent on its C-terminal RS- and RD/E-rich region but is independent of the phosphorylation status of Ser-453 and Ser-604 within this region. The unique N-terminal SAP-motif of Acinus-L is responsible for its diffuse localization in the nucleus. Moreover, the sub-nuclear localization of Acinus isoforms is affected by each other, which is determined by the combinatorial effect of the more potent SAP motif of Acinus-L and the C-terminal RS- and RD/E-rich region in all Acinus isoforms. The C-terminal RS- and RD/E-rich region of Acinus mediates the colocalization of Acinus isoforms as well as with its interacting protein RNPS1. In conclusion, the SAP motif is responsible for the difference in the nuclear localization between Acinus-L and Acinus-S′. This difference in the nuclear localization of Acinus-S′ and Acinus-L may suggest that these two isoforms have different functional roles.
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The SAP Motif and C‐Terminal RS‐ and RD/E‐Rich Region Influences the Sub‐Nuclear Localization of Acinus Isoforms
Journal of cellular biochemistry, 2014Co-Authors: Fang Wang, Karen S. Wendling, Kenneth J. Soprano, Dianne Robert SopranoAbstract:Acinus has been reported to function in apoptosis, RNA processing and regulation of gene transcription including RA-dependent transcription. There are three different isoforms of Acinus termed Acinus-L, Acinus-S′ and Acinus-S. The isoforms of Acinus differ in their N-terminus while the C-terminus is consistent in all isoforms. The sub-nuclear localization of Acinus-L and Acinus-S′ was determined using fluorescence microscopy. Acinus-S′ colocalizes with SC35 in nuclear speckles while Acinus-L localizes diffusely throughout the nucleoplasm. RA treatment has little effect on the sub-nuclear localization of Acinus-L and Acinus-S′. The domains/regions necessary for the distinct sub-nuclear localization of Acinus-L and Acinus-S′ were identified. The speckled sub-nuclear localization of Acinus-S′ is dependent on its C-terminal RS- and RD/E-rich region but is independent of the phosphorylation status of Ser-453 and Ser-604 within this region. The unique N-terminal SAP-motif of Acinus-L is responsible for its diffuse localization in the nucleus. Moreover, the sub-nuclear localization of Acinus isoforms is affected by each other, which is determined by the combinatorial effect of the more potent SAP motif of Acinus-L and the C-terminal RS- and RD/E-rich region in all Acinus isoforms. The C-terminal RS- and RD/E-rich region of Acinus mediates the colocalization of Acinus isoforms as well as with its interacting protein RNPS1. In conclusion, the SAP motif is responsible for the difference in the nuclear localization between Acinus-L and Acinus-S′. This difference in the nuclear localization of Acinus-S′ and Acinus-L may suggest that these two isoforms have different functional roles.
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Acinus-S' represses retinoic acid receptor (RAR)-regulated gene expression through interaction with the B domains of RARs.
Molecular and cellular biology, 2008Co-Authors: Zivjena Vucetic, Fang Wang, Kenneth J. Soprano, Zhen-ping Zhang, Jianhua Zhao, Dianne Robert SopranoAbstract:The diverse biological actions of retinoic acid (RA) are mediated by RA receptors (RARs) and retinoid X receptors (RXRs). Modulation of transcription by RARs/RXRs is achieved through two activation functions, ligand-independent AF-1 and ligand-dependent AF-2, located in the A/B and E domains, respectively. While the coregulatory proteins that interact with the E domain are well studied, the A/B domain-interacting partners and their influence(s) on the function of RARs are poorly understood. Acinus-S′ is an ubiquitous nuclear protein that has been implicated in inducing apoptotic chromatin condensation and regulating mRNA processing. Our data demonstrate that Acinus-S′ can specifically repress ligand-independent and ligand-dependent expression of a DR5 RA response element(RARE)-dependent reporter gene and several endogenous RAR-regulated genes in a dose-dependent and gene-specific manner. Chromatin immunoprecipitation assays show that Acinus-S′ associates with RAREs within the promoters of endogenous genes independent of RA treatment. Furthermore, the C-terminal end of Acinus-S′ and the B domain of RARβ interact independently of ligand, and the C-terminal end of Acinus-S′ is sufficient for the repression of RAR-regulated gene expression. Finally, histone deacetylase activity only partially accounts for the repressive effect of Acinus-S′ on RAR-dependent gene expression. These findings identify Acinus-S′ as a novel RAR-interacting protein that regulates the expression of a subset of RAR-regulated genes through direct binding to the N-terminal B domains of RARs.
Fang Wang - One of the best experts on this subject based on the ideXlab platform.
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Role of Acinus in regulating retinoic acid-responsive gene pre-mRNA splicing.
Journal of cellular physiology, 2014Co-Authors: Fang Wang, Kenneth J. Soprano, Dianne Robert SopranoAbstract:Acinus-S’ is a corepressor for retinoic acid receptor (RAR)-dependent gene transcription and has been suggested to be involved in RNA processing. In this study, the role of Acinus isoforms in regulating pre-mRNA splicing was explored using in vivo splicing assays. Both Acinus-L and Acinus-S’, with the activity of Acinus-L higher than that of Acinus-S’, increase the splicing of a retinoic acid (RA)-responsive minigene containing a weak 5′ splice site but not a RA-responsive minigene containing a strong 5′ splice site. RA treatment further enhances the splicing of the weak 5′ splice site by Acinus in a dose- and time-dependent manner, suggesting a RA-dependent activity in addition to a RA-independent activity of Acinus. The RA-independent effect of Acinus occurs to varying degrees using minigene constructs containing several different promoters, while the RA-dependent splicing activity of Acinus is specific for transcripts derived from the minigene driven by a RA response element (RARE)-containing promoter. This suggests that the ligand-dependent splicing activity of Acinus is related to the RA-activated RAR bound to the RARE. The RRM domain is necessary for the RA-dependent splicing activity of Acinus and the RA-independent splicing activity of Acinus is repressed by RNPS1. Importantly, measurement of the splicing of endogenous human RARβ and Bcl-x in vivo demonstrates that Acinus stimulates the use of the weaker alternative 5′ splice site of these two genes in a RA-dependent manner for RARβ and a RA-independent manner for Bcl-x. Taken together, these studies demonstrate that Acinus functions in both RAR-dependent splicing and RAR-dependent transcription. J. Cell. Physiol. 230: 791–801, 2015. © 2014 Wiley Periodicals, Inc.
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the sap motif and c terminal rs and rd e rich region influences the sub nuclear localization of Acinus isoforms
Journal of Cellular Biochemistry, 2014Co-Authors: Fang Wang, Karen S. Wendling, Kenneth J. Soprano, Dianne Robert SopranoAbstract:Acinus has been reported to function in apoptosis, RNA processing and regulation of gene transcription including RA-dependent transcription. There are three different isoforms of Acinus termed Acinus-L, Acinus-S′ and Acinus-S. The isoforms of Acinus differ in their N-terminus while the C-terminus is consistent in all isoforms. The sub-nuclear localization of Acinus-L and Acinus-S′ was determined using fluorescence microscopy. Acinus-S′ colocalizes with SC35 in nuclear speckles while Acinus-L localizes diffusely throughout the nucleoplasm. RA treatment has little effect on the sub-nuclear localization of Acinus-L and Acinus-S′. The domains/regions necessary for the distinct sub-nuclear localization of Acinus-L and Acinus-S′ were identified. The speckled sub-nuclear localization of Acinus-S′ is dependent on its C-terminal RS- and RD/E-rich region but is independent of the phosphorylation status of Ser-453 and Ser-604 within this region. The unique N-terminal SAP-motif of Acinus-L is responsible for its diffuse localization in the nucleus. Moreover, the sub-nuclear localization of Acinus isoforms is affected by each other, which is determined by the combinatorial effect of the more potent SAP motif of Acinus-L and the C-terminal RS- and RD/E-rich region in all Acinus isoforms. The C-terminal RS- and RD/E-rich region of Acinus mediates the colocalization of Acinus isoforms as well as with its interacting protein RNPS1. In conclusion, the SAP motif is responsible for the difference in the nuclear localization between Acinus-L and Acinus-S′. This difference in the nuclear localization of Acinus-S′ and Acinus-L may suggest that these two isoforms have different functional roles.
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The SAP Motif and C‐Terminal RS‐ and RD/E‐Rich Region Influences the Sub‐Nuclear Localization of Acinus Isoforms
Journal of cellular biochemistry, 2014Co-Authors: Fang Wang, Karen S. Wendling, Kenneth J. Soprano, Dianne Robert SopranoAbstract:Acinus has been reported to function in apoptosis, RNA processing and regulation of gene transcription including RA-dependent transcription. There are three different isoforms of Acinus termed Acinus-L, Acinus-S′ and Acinus-S. The isoforms of Acinus differ in their N-terminus while the C-terminus is consistent in all isoforms. The sub-nuclear localization of Acinus-L and Acinus-S′ was determined using fluorescence microscopy. Acinus-S′ colocalizes with SC35 in nuclear speckles while Acinus-L localizes diffusely throughout the nucleoplasm. RA treatment has little effect on the sub-nuclear localization of Acinus-L and Acinus-S′. The domains/regions necessary for the distinct sub-nuclear localization of Acinus-L and Acinus-S′ were identified. The speckled sub-nuclear localization of Acinus-S′ is dependent on its C-terminal RS- and RD/E-rich region but is independent of the phosphorylation status of Ser-453 and Ser-604 within this region. The unique N-terminal SAP-motif of Acinus-L is responsible for its diffuse localization in the nucleus. Moreover, the sub-nuclear localization of Acinus isoforms is affected by each other, which is determined by the combinatorial effect of the more potent SAP motif of Acinus-L and the C-terminal RS- and RD/E-rich region in all Acinus isoforms. The C-terminal RS- and RD/E-rich region of Acinus mediates the colocalization of Acinus isoforms as well as with its interacting protein RNPS1. In conclusion, the SAP motif is responsible for the difference in the nuclear localization between Acinus-L and Acinus-S′. This difference in the nuclear localization of Acinus-S′ and Acinus-L may suggest that these two isoforms have different functional roles.
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Acinus-S' represses retinoic acid receptor (RAR)-regulated gene expression through interaction with the B domains of RARs.
Molecular and cellular biology, 2008Co-Authors: Zivjena Vucetic, Fang Wang, Kenneth J. Soprano, Zhen-ping Zhang, Jianhua Zhao, Dianne Robert SopranoAbstract:The diverse biological actions of retinoic acid (RA) are mediated by RA receptors (RARs) and retinoid X receptors (RXRs). Modulation of transcription by RARs/RXRs is achieved through two activation functions, ligand-independent AF-1 and ligand-dependent AF-2, located in the A/B and E domains, respectively. While the coregulatory proteins that interact with the E domain are well studied, the A/B domain-interacting partners and their influence(s) on the function of RARs are poorly understood. Acinus-S′ is an ubiquitous nuclear protein that has been implicated in inducing apoptotic chromatin condensation and regulating mRNA processing. Our data demonstrate that Acinus-S′ can specifically repress ligand-independent and ligand-dependent expression of a DR5 RA response element(RARE)-dependent reporter gene and several endogenous RAR-regulated genes in a dose-dependent and gene-specific manner. Chromatin immunoprecipitation assays show that Acinus-S′ associates with RAREs within the promoters of endogenous genes independent of RA treatment. Furthermore, the C-terminal end of Acinus-S′ and the B domain of RARβ interact independently of ligand, and the C-terminal end of Acinus-S′ is sufficient for the repression of RAR-regulated gene expression. Finally, histone deacetylase activity only partially accounts for the repressive effect of Acinus-S′ on RAR-dependent gene expression. These findings identify Acinus-S′ as a novel RAR-interacting protein that regulates the expression of a subset of RAR-regulated genes through direct binding to the N-terminal B domains of RARs.
Kenneth J. Soprano - One of the best experts on this subject based on the ideXlab platform.
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Role of Acinus in regulating retinoic acid-responsive gene pre-mRNA splicing.
Journal of cellular physiology, 2014Co-Authors: Fang Wang, Kenneth J. Soprano, Dianne Robert SopranoAbstract:Acinus-S’ is a corepressor for retinoic acid receptor (RAR)-dependent gene transcription and has been suggested to be involved in RNA processing. In this study, the role of Acinus isoforms in regulating pre-mRNA splicing was explored using in vivo splicing assays. Both Acinus-L and Acinus-S’, with the activity of Acinus-L higher than that of Acinus-S’, increase the splicing of a retinoic acid (RA)-responsive minigene containing a weak 5′ splice site but not a RA-responsive minigene containing a strong 5′ splice site. RA treatment further enhances the splicing of the weak 5′ splice site by Acinus in a dose- and time-dependent manner, suggesting a RA-dependent activity in addition to a RA-independent activity of Acinus. The RA-independent effect of Acinus occurs to varying degrees using minigene constructs containing several different promoters, while the RA-dependent splicing activity of Acinus is specific for transcripts derived from the minigene driven by a RA response element (RARE)-containing promoter. This suggests that the ligand-dependent splicing activity of Acinus is related to the RA-activated RAR bound to the RARE. The RRM domain is necessary for the RA-dependent splicing activity of Acinus and the RA-independent splicing activity of Acinus is repressed by RNPS1. Importantly, measurement of the splicing of endogenous human RARβ and Bcl-x in vivo demonstrates that Acinus stimulates the use of the weaker alternative 5′ splice site of these two genes in a RA-dependent manner for RARβ and a RA-independent manner for Bcl-x. Taken together, these studies demonstrate that Acinus functions in both RAR-dependent splicing and RAR-dependent transcription. J. Cell. Physiol. 230: 791–801, 2015. © 2014 Wiley Periodicals, Inc.
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the sap motif and c terminal rs and rd e rich region influences the sub nuclear localization of Acinus isoforms
Journal of Cellular Biochemistry, 2014Co-Authors: Fang Wang, Karen S. Wendling, Kenneth J. Soprano, Dianne Robert SopranoAbstract:Acinus has been reported to function in apoptosis, RNA processing and regulation of gene transcription including RA-dependent transcription. There are three different isoforms of Acinus termed Acinus-L, Acinus-S′ and Acinus-S. The isoforms of Acinus differ in their N-terminus while the C-terminus is consistent in all isoforms. The sub-nuclear localization of Acinus-L and Acinus-S′ was determined using fluorescence microscopy. Acinus-S′ colocalizes with SC35 in nuclear speckles while Acinus-L localizes diffusely throughout the nucleoplasm. RA treatment has little effect on the sub-nuclear localization of Acinus-L and Acinus-S′. The domains/regions necessary for the distinct sub-nuclear localization of Acinus-L and Acinus-S′ were identified. The speckled sub-nuclear localization of Acinus-S′ is dependent on its C-terminal RS- and RD/E-rich region but is independent of the phosphorylation status of Ser-453 and Ser-604 within this region. The unique N-terminal SAP-motif of Acinus-L is responsible for its diffuse localization in the nucleus. Moreover, the sub-nuclear localization of Acinus isoforms is affected by each other, which is determined by the combinatorial effect of the more potent SAP motif of Acinus-L and the C-terminal RS- and RD/E-rich region in all Acinus isoforms. The C-terminal RS- and RD/E-rich region of Acinus mediates the colocalization of Acinus isoforms as well as with its interacting protein RNPS1. In conclusion, the SAP motif is responsible for the difference in the nuclear localization between Acinus-L and Acinus-S′. This difference in the nuclear localization of Acinus-S′ and Acinus-L may suggest that these two isoforms have different functional roles.
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The SAP Motif and C‐Terminal RS‐ and RD/E‐Rich Region Influences the Sub‐Nuclear Localization of Acinus Isoforms
Journal of cellular biochemistry, 2014Co-Authors: Fang Wang, Karen S. Wendling, Kenneth J. Soprano, Dianne Robert SopranoAbstract:Acinus has been reported to function in apoptosis, RNA processing and regulation of gene transcription including RA-dependent transcription. There are three different isoforms of Acinus termed Acinus-L, Acinus-S′ and Acinus-S. The isoforms of Acinus differ in their N-terminus while the C-terminus is consistent in all isoforms. The sub-nuclear localization of Acinus-L and Acinus-S′ was determined using fluorescence microscopy. Acinus-S′ colocalizes with SC35 in nuclear speckles while Acinus-L localizes diffusely throughout the nucleoplasm. RA treatment has little effect on the sub-nuclear localization of Acinus-L and Acinus-S′. The domains/regions necessary for the distinct sub-nuclear localization of Acinus-L and Acinus-S′ were identified. The speckled sub-nuclear localization of Acinus-S′ is dependent on its C-terminal RS- and RD/E-rich region but is independent of the phosphorylation status of Ser-453 and Ser-604 within this region. The unique N-terminal SAP-motif of Acinus-L is responsible for its diffuse localization in the nucleus. Moreover, the sub-nuclear localization of Acinus isoforms is affected by each other, which is determined by the combinatorial effect of the more potent SAP motif of Acinus-L and the C-terminal RS- and RD/E-rich region in all Acinus isoforms. The C-terminal RS- and RD/E-rich region of Acinus mediates the colocalization of Acinus isoforms as well as with its interacting protein RNPS1. In conclusion, the SAP motif is responsible for the difference in the nuclear localization between Acinus-L and Acinus-S′. This difference in the nuclear localization of Acinus-S′ and Acinus-L may suggest that these two isoforms have different functional roles.
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Acinus-S' represses retinoic acid receptor (RAR)-regulated gene expression through interaction with the B domains of RARs.
Molecular and cellular biology, 2008Co-Authors: Zivjena Vucetic, Fang Wang, Kenneth J. Soprano, Zhen-ping Zhang, Jianhua Zhao, Dianne Robert SopranoAbstract:The diverse biological actions of retinoic acid (RA) are mediated by RA receptors (RARs) and retinoid X receptors (RXRs). Modulation of transcription by RARs/RXRs is achieved through two activation functions, ligand-independent AF-1 and ligand-dependent AF-2, located in the A/B and E domains, respectively. While the coregulatory proteins that interact with the E domain are well studied, the A/B domain-interacting partners and their influence(s) on the function of RARs are poorly understood. Acinus-S′ is an ubiquitous nuclear protein that has been implicated in inducing apoptotic chromatin condensation and regulating mRNA processing. Our data demonstrate that Acinus-S′ can specifically repress ligand-independent and ligand-dependent expression of a DR5 RA response element(RARE)-dependent reporter gene and several endogenous RAR-regulated genes in a dose-dependent and gene-specific manner. Chromatin immunoprecipitation assays show that Acinus-S′ associates with RAREs within the promoters of endogenous genes independent of RA treatment. Furthermore, the C-terminal end of Acinus-S′ and the B domain of RARβ interact independently of ligand, and the C-terminal end of Acinus-S′ is sufficient for the repression of RAR-regulated gene expression. Finally, histone deacetylase activity only partially accounts for the repressive effect of Acinus-S′ on RAR-dependent gene expression. These findings identify Acinus-S′ as a novel RAR-interacting protein that regulates the expression of a subset of RAR-regulated genes through direct binding to the N-terminal B domains of RARs.
J Chen - One of the best experts on this subject based on the ideXlab platform.
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NGF inhibits human leukemia proliferation by downregulating cyclin A1 expression through promoting Acinus/CtBP2. Oncogene 2009
2016Co-Authors: C B Chan, Xia Liu, I Williams, Sungwuk Jang, Stephen Ihong Hsu, J ChenAbstract:Cyclin A1 is essential for leukemia progression, and its expression is tightly regulated by Acinus, a nuclear speckle protein. However, the molecular mechanism of how Acinus mediates cyclin A1 expression remains elusive. Here we show that transcription corepressor CtBP2 directly binds Acinus, which is regulated by NGF, inhibiting its stimulatory effect on cyclin A1 but not cyclin A2 expression in leukemia. NGF, a cognate ligand for the neurotrophic receptor TrkA, promotes the interaction between CtBP2 and Acinus through triggering Acinus phosphorylation by Akt. Overexpression of CtBP2 diminishes cyclin A1 transcription, whereas depletion of CtBP2 abolishes NGF’s suppressive effect on cyclin A1 expression. Strikingly, gambogic amide, a newly identified TrkA agonist, potently represses cyclin A1 expression, thus blocking K562 cell proliferation. Moreover, gambogic amide ameliorates the leukemia progression in K562 cells inoculated nude mice. Hence, NGF down-regulates cyclin A1 expression through escalating CtBP2/Acinus complex formation, and gambogic amide might be useful for human leukemia treatment
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NGF inhibits human leukemia proliferation by downregulating cyclin A1 expression through promoting Acinus/CtBP2 association
Oncogene, 2009Co-Authors: C B Chan, S -w Jang, I Williams, S Kang, J Chen, K YeAbstract:Cyclin A1 is essential for leukemia progression, and its expression is tightly regulated by Acinus, a nuclear speckle protein. However, the molecular mechanism of how Acinus mediates cyclin A1 expression remains elusive. Here we show that transcription corepressor CtBP2 directly binds Acinus, which is regulated by nerve growth factor (NGF), inhibiting its stimulatory effect on cyclin A1, but not cyclin A2, expression in leukemia. NGF, a cognate ligand for the neurotrophic receptor TrkA, promotes the interaction between CtBP2 and Acinus through triggering Acinus phosphorylation by Akt. Overexpression of CtBP2 diminishes cyclin A1 transcription, whereas depletion of CtBP2 abolishes NGF's suppressive effect on cyclin A1 expression. Strikingly, gambogic amide, a newly identified TrkA agonist, potently represses cyclin A1 expression, thus blocking K562 cell proliferation. Moreover, gambogic amide ameliorates the leukemia progression in K562 cells inoculated nude mice. Hence, NGF downregulates cyclin A1 expression through escalating CtBP2/Acinus complex formation, and gambogic amide might be useful for human leukemia treatment.
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ngf inhibits human leukemia proliferation by downregulating cyclin a1 expression through promoting Acinus ctbp2 association
Oncogene, 2009Co-Authors: C B Chan, Xia Liu, S Kang, Sungwuk Jang, Stephen Ihong Hsu, Ifor R Williams, J ChenAbstract:Cyclin A1 is essential for leukemia progression, and its expression is tightly regulated by Acinus, a nuclear speckle protein. However, the molecular mechanism of how Acinus mediates cyclin A1 expression remains elusive. Here we show that transcription corepressor CtBP2 directly binds Acinus, which is regulated by nerve growth factor (NGF), inhibiting its stimulatory effect on cyclin A1, but not cyclin A2, expression in leukemia. NGF, a cognate ligand for the neurotrophic receptor TrkA, promotes the interaction between CtBP2 and Acinus through triggering Acinus phosphorylation by Akt. Overexpression of CtBP2 diminishes cyclin A1 transcription, whereas depletion of CtBP2 abolishes NGF's suppressive effect on cyclin A1 expression. Strikingly, gambogic amide, a newly identified TrkA agonist, potently represses cyclin A1 expression, thus blocking K562 cell proliferation. Moreover, gambogic amide ameliorates the leukemia progression in K562 cells inoculated nude mice. Hence, NGF downregulates cyclin A1 expression through escalating CtBP2/Acinus complex formation, and gambogic amide might be useful for human leukemia treatment.
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Serine/arginine protein-specific kinase 2 promotes leukemia cell proliferation by phosphorylating Acinus and regulating cyclin A1.
Cancer research, 2008Co-Authors: Sungwuk Jang, J Chen, Seung-ju Yang, Åsa Ehlén, Shaozhong Dong, Hanna Khoury, Jenny L. PerssonAbstract:Serine/arginine (SR) protein-specific kinase (SRPK), a family of cell cycle-regulated protein kinases, phosphorylate SR domain-containing proteins in nuclear speckles and mediate the pre-mRNA splicing. However, the physiologic roles of this event in cell cycle are incompletely understood. Here, we show that SRPK2 binds and phosphorylates Acinus, an SR protein essential for RNA splicing, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin A1 but not A2 up-regulation. Acinus S422D, an SRPK2 phosphorylation mimetic, enhances cyclin A1 transcription, whereas Acinus S422A, an unphosphorylatable mutant, blocks the stimulatory effect of SRPK2. Ablation of Acinus or SRPK2 abrogates cyclin A1 expression in leukemia cells and arrest cells at G, phase. Overexpression of Acinus or SRPK2 increases leukemia cell proliferation. Furthermore, both SRPK2 and Acinus are overexpressed in some human acute myelogenous leukemia patients and correlate with elevated cyclin A1 expression levels, fitting with the oncogenic activity of cyclin A1 in leukemia. Thus, our findings establish a molecular mechanism by which SR splicing machinery regulates cell cycle and contributes to leukemia tumorigenesis. (Less)
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serine arginine protein specific kinase 2 promotes leukemia cell proliferation by phosphorylating Acinus and regulating cyclin a1
Cancer Research, 2008Co-Authors: Sungwuk Jang, J Chen, Seung-ju Yang, Åsa Ehlén, Shaozhong Dong, Hanna Khoury, Jenny L. PerssonAbstract:Serine/arginine (SR) protein-specific kinase (SRPK), a family of cell cycle-regulated protein kinases, phosphorylate SR domain-containing proteins in nuclear speckles and mediate the pre-mRNA splicing. However, the physiologic roles of this event in cell cycle are incompletely understood. Here, we show that SRPK2 binds and phosphorylates Acinus, an SR protein essential for RNA splicing, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin A1 but not A2 up-regulation. Acinus S422D, an SRPK2 phosphorylation mimetic, enhances cyclin A1 transcription, whereas Acinus S422A, an unphosphorylatable mutant, blocks the stimulatory effect of SRPK2. Ablation of Acinus or SRPK2 abrogates cyclin A1 expression in leukemia cells and arrest cells at G, phase. Overexpression of Acinus or SRPK2 increases leukemia cell proliferation. Furthermore, both SRPK2 and Acinus are overexpressed in some human acute myelogenous leukemia patients and correlate with elevated cyclin A1 expression levels, fitting with the oncogenic activity of cyclin A1 in leukemia. Thus, our findings establish a molecular mechanism by which SR splicing machinery regulates cell cycle and contributes to leukemia tumorigenesis. (Less)
Jenny L. Persson - One of the best experts on this subject based on the ideXlab platform.
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Serine/arginine protein-specific kinase 2 promotes leukemia cell proliferation by phosphorylating Acinus and regulating cyclin A1.
Cancer research, 2008Co-Authors: Sungwuk Jang, J Chen, Seung-ju Yang, Åsa Ehlén, Shaozhong Dong, Hanna Khoury, Jenny L. PerssonAbstract:Serine/arginine (SR) protein-specific kinase (SRPK), a family of cell cycle-regulated protein kinases, phosphorylate SR domain-containing proteins in nuclear speckles and mediate the pre-mRNA splicing. However, the physiologic roles of this event in cell cycle are incompletely understood. Here, we show that SRPK2 binds and phosphorylates Acinus, an SR protein essential for RNA splicing, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin A1 but not A2 up-regulation. Acinus S422D, an SRPK2 phosphorylation mimetic, enhances cyclin A1 transcription, whereas Acinus S422A, an unphosphorylatable mutant, blocks the stimulatory effect of SRPK2. Ablation of Acinus or SRPK2 abrogates cyclin A1 expression in leukemia cells and arrest cells at G, phase. Overexpression of Acinus or SRPK2 increases leukemia cell proliferation. Furthermore, both SRPK2 and Acinus are overexpressed in some human acute myelogenous leukemia patients and correlate with elevated cyclin A1 expression levels, fitting with the oncogenic activity of cyclin A1 in leukemia. Thus, our findings establish a molecular mechanism by which SR splicing machinery regulates cell cycle and contributes to leukemia tumorigenesis. (Less)
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serine arginine protein specific kinase 2 promotes leukemia cell proliferation by phosphorylating Acinus and regulating cyclin a1
Cancer Research, 2008Co-Authors: Sungwuk Jang, J Chen, Seung-ju Yang, Åsa Ehlén, Shaozhong Dong, Hanna Khoury, Jenny L. PerssonAbstract:Serine/arginine (SR) protein-specific kinase (SRPK), a family of cell cycle-regulated protein kinases, phosphorylate SR domain-containing proteins in nuclear speckles and mediate the pre-mRNA splicing. However, the physiologic roles of this event in cell cycle are incompletely understood. Here, we show that SRPK2 binds and phosphorylates Acinus, an SR protein essential for RNA splicing, and redistributes it from the nuclear speckles to the nucleoplasm, resulting in cyclin A1 but not A2 up-regulation. Acinus S422D, an SRPK2 phosphorylation mimetic, enhances cyclin A1 transcription, whereas Acinus S422A, an unphosphorylatable mutant, blocks the stimulatory effect of SRPK2. Ablation of Acinus or SRPK2 abrogates cyclin A1 expression in leukemia cells and arrest cells at G, phase. Overexpression of Acinus or SRPK2 increases leukemia cell proliferation. Furthermore, both SRPK2 and Acinus are overexpressed in some human acute myelogenous leukemia patients and correlate with elevated cyclin A1 expression levels, fitting with the oncogenic activity of cyclin A1 in leukemia. Thus, our findings establish a molecular mechanism by which SR splicing machinery regulates cell cycle and contributes to leukemia tumorigenesis. (Less)