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Hung Ying Kao - One of the best experts on this subject based on the ideXlab platform.
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ablation of Promyelocytic Leukemia Protein pml re patterns energy balance and protects mice from obesity induced by a western diet
Journal of Biological Chemistry, 2013Co-Authors: Xiwen Cheng, Yu Liu, Shuang Guo, Hao Chu, Parvin Hakimi, Nathan A Berger, Richard W Hanson, Hung Ying KaoAbstract:The Promyelocytic Leukemia Protein is a well known tumor suppressor, but its role in metabolism is largely unknown. Mice with a deletion in the gene for PML (KO mice) exhibit altered gene expression in liver, adipose tissue, and skeletal muscle, an accelerated rate of fatty acid metabolism, abnormal glucose metabolism, constitutive AMP-activating kinase (AMPK) activation, and insulin resistance in skeletal muscle. Last, an increased rate of energy expenditure protects PML KO mice from the effects of obesity induced by a Western diet. Collectively, our study uncovers a previously unappreciated role of PML in the regulation of metabolism and energy balance in mice.
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Promyelocytic Leukemia Protein pml regulates endothelial cell network formation and migration in response to tumor necrosis factor α tnfα and interferon α ifnα
Journal of Biological Chemistry, 2012Co-Authors: Xiwen Cheng, Yu Liu, Hao Chu, Hung Ying KaoAbstract:Promyelocytic Leukemia Protein (PML) is a tumor suppressor that is highly expressed in vascular endothelium and inflamed tissues, yet its role in inflammation-associated cytokine-regulated angiogenesis and underlying mechanism remains largely unclear. We show that tumor necrosis factor α (TNFα) and interferon α (IFNα) stimulate PML expression while suppressing EC network formation and migration, two key events during angiogenesis. By a knockdown approach, we demonstrate that PML is indispensable for TNFα- and IFNα-mediated inhibition of EC network formation. We further demonstrate that signal transducer and activator of transcription 1 (STAT1) binds PML promoter and that is an important regulator of PML expression. Knockdown of STAT1 reduces endogenous PML and blocks TNFα- and IFNα-induced PML accumulation and relieves TNFα- and IFNα-mediated inhibition of EC network formation. Our data also indicate that PML regulates EC migration, in part, by modulating expression of downstream genes, such as negatively regulating integrin β1 (ITGB1). In addition, knockdown of STAT1 or PML alleviates TNFα- and IFNα-mediated inhibition of ITGB1 expression. Antibody blockade demonstrates that ITGB1 is functionally important for PML- and STAT1-regulated EC migration. Taken together, our data provide novel mechanistic insights that PML functions as a negative regulator in EC network formation and migration.
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mitogen activated Protein kinase extracellular signal regulated kinase 2 phosphorylates and promotes pin1 Protein dependent Promyelocytic Leukemia Protein turnover
Journal of Biological Chemistry, 2011Co-Authors: Jun Hee Lim, Erin L Reineke, Yu Liu, Hung Ying KaoAbstract:The Promyelocytic Leukemia (PML) Protein is a tumor suppressor that has an important role in several cellular processes, including apoptosis, viral infection, DNA damage repair, cell cycle regulation, and senescence. PML is an essential component of sub-nuclear structures called PML nuclear bodies (NBs). Our laboratory has previously demonstrated that the peptidyl-prolyl cis-trans isomerase, Pin1, binds and targets PML for degradation in a phosphorylation-dependent manner. To further elucidate the mechanisms underlying Pin1-mediated PML degradation, we aimed to identify one or more factors that promote PML phosphorylation. Here we show that treatment with U0126, an inhibitor of the ERK2 upstream kinases MEK1/2, leads to an increase in PML Protein accumulation and an inhibition of the interaction between Pin1 and PML in MDA-MB-231 breast cancer cells. Consistent with this observation, phosphorylated ERK2 partially co-localized with PML NBs. Although U0126 up-regulated exogenous wild-type PML levels, it did not have an effect on the steady-state level of a mutant form of PML that is defective in binding Pin1. In addition, exogenous wild-type, but not Pin1 binding-defective PML Protein expression levels were decreased by overexpression of ERK2. In contrast, knockdown of ERK2 by siRNA resulted in an increase in PML Protein levels and an increase in the formation of PML NBs. Using phospho-specific antibodies, we identified Ser-403 and Ser-505 as the ERK2 targets that promote Pin1-mediated PML degradation. Finally, we demonstrated that EGF induced activation of ERK and interaction between PML and phosphorylated ERK resulting in a decrease in PML Protein levels. Taken together, our results support a model in which Pin1 promotes PML degradation in an ERK2-dependent manner.
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Promyelocytic Leukemia Protein controls cell migration in response to hydrogen peroxide and insulin like growth factor 1
Journal of Biological Chemistry, 2010Co-Authors: Erin L Reineke, Yu Liu, Hung Ying KaoAbstract:Promyelocytic Leukemia Protein (PML) was originally identified as part of a chromosomal translocation that contributes to the development of acute Promyelocytic Leukemia (APL). Since its discovery, PML has been found to play diverse roles in different cellular processes. Notably, PML has anti-proliferative and pro-apoptotic activity that supports its role as a tumor suppressor. We have previously shown that the peptidyl-prolyl isomerase Pin1 is able to affect cell proliferation and hydrogen peroxide (H2O2)-mediated cell death through modulation of the steady-state levels of PML. We have extended these studies to show that the interaction between PML and Pin1 is targeted by multiple extracellular signals in the cell. We show that H2O2 up-regulates and IGF-1 down-regulates PML expression in a Pin1-dependent manner. Interestingly, we found that H2O2- and IGF-1-mediated alteration in PML accumulation regulate MDA-MB-231 cell migration. Furthermore, we show that the control of cell migration by PML, and thus H2O2 and IGF-1, results from PML-dependent decreased expression of integrin β1 (ITGB1). Knockdown of Pin1 leads to decreased cell migration, lower levels of ITGB1 expression and resistance to IGF-1- and H2O2-induced changes in cell migration and ITGB1 expression. Taken together, our work identifies PML as a common target for H2O2 and IGF-1 and supports a novel tumor suppressive role for PML in controlling cell migration through the expression of ITGB1.
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targeting Promyelocytic Leukemia Protein a means to regulating pml nuclear bodies
International Journal of Biological Sciences, 2009Co-Authors: Erin L Reineke, Hung Ying KaoAbstract:The Promyelocytic Leukemia Protein (PML) is involved in many cellular processes including cell cycle progression, DNA damage response, transcriptional regulation, viral infection, and apoptosis. These cellular activities often rely on the localization of PML to unique subnuclear structures known as PML nuclear bodies (NBs). More than 50 cellular Proteins are known to traffic in and out of PML NBs, either transiently or constitutively. In order to understand the dynamics of these NBs, it is important to delineate the regulation of PML itself. PML is subject to extensive regulation at transcriptional, post-transcriptional, and post-translational levels. Many of these modes of regulation depend on the cellular context and the presence of extracellular signals. This review focuses on the current knowledge of regulation of PML under normal cellular conditions as well as the role for regulation of PML in viral infection and cancer.
Pier Paolo Pandolfi - One of the best experts on this subject based on the ideXlab platform.
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Promyelocytic Leukemia Protein interacts with the apoptosis associated speck like Protein to limit inflammasome activation
Journal of Biological Chemistry, 2014Co-Authors: Jennifer K Dowling, Pier Paolo Pandolfi, Christine Becker, Nollaig M Bourke, Sinead C Corr, Dympna J Connolly, Susan R Quinn, Ashley Mansell, Luke A J OneillAbstract:The apoptosis-associated speck-like Protein containing a caspase-activating recruitment domain (ASC) is an essential component of several inflammasomes, multiProtein complexes that regulate caspase-1 activation and inflammation. We report here an interaction between Promyelocytic Leukemia Protein (PML) and ASC. We observed enhanced formation of ASC dimers in PML-deficient macrophages. These macrophages also display enhanced levels of ASC in the cytosol. Furthermore, IL-1β production was markedly enhanced in these macrophages in response to both NLRP3 and AIM2 inflammasome activation and following bone marrow-derived macrophage infection with herpes simplex virus-1 (HSV-1) and Salmonella typhimurium. Collectively, our data indicate that PML limits ASC function, retaining ASC in the nucleus.
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synergy against pml rara targeting transcription proteolysis differentiation and self renewal in acute Promyelocytic Leukemia
Journal of Experimental Medicine, 2013Co-Authors: Guilherme Augusto Dos Santos, Lev Kats, Pier Paolo PandolfiAbstract:Acute Promyelocytic Leukemia (APL) is a hematological malignancy driven by a chimeric oncoProtein containing the C terminus of the retinoic acid receptor-a (RARa) fused to an N-terminal partner, most commonly Promyelocytic Leukemia Protein (PML). Mechanistically, PML-RARa acts as a transcriptional repressor of RARa and non-RARa target genes and antagonizes the formation and function of PML nuclear bodies that regulate numerous signaling pathways. The empirical discoveries that PML-RARa–associated APL is sensitive to both all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO), and the subsequent understanding of the mechanisms of action of these drugs, have led to efforts to understand the contribution of molecular events to APL cell differentiation, Leukemia-initiating cell (LIC) clearance, and disease eradication in vitro and in vivo. Critically, the mechanistic insights gleaned from these studies have resulted not only in a better understanding of APL itself, but also carry valuable lessons for other malignancies.
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a pml ppar δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance
Nature Medicine, 2012Co-Authors: Arkaitz Carracedo, Dror Weiss, Fumio Arai, David Avigan, Zachary T Schafer, Ronald M Evans, Toshio Suda, Pier Paolo PandolfiAbstract:Keisuke Ito et al. uncover a new pathway regulating hematopoietic stem cell maintenance and function. In this pathway, the Promyelocytic Leukemia Protein (PML) regulates the activity of the PPAR-δ nuclear hormone receptor and, thereby, fatty acid oxidation, such that PPAR-δ activators have the potential of improving stem cell function. Intriguingly, this pathway controls the cell fate of dividing stem cells.
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Promyelocytic Leukemia zinc finger Protein regulates interferon mediated innate immunity
Immunity, 2009Co-Authors: Dakang Xu, Pier Paolo Pandolfi, Michelle Holko, Anthony J Sadler, Bernadette Scott, Shigeki Higashiyama, Windy Berkofskyfessler, Melanie J Mcconnell, Jonathan D Licht, Bryan R G WilliamsAbstract:Interferons (IFNs) direct innate and acquired immune responses and, accordingly, are used therapeutically to treat a number of diseases, yet the diverse effects they elicit are not fully understood. Here, we identified the Promyelocytic Leukemia zinc finger (PLZF) Protein as a previously unrecognized component of the IFN response. IFN stimulated an association of PLZF with Promyelocytic Leukemia Protein (PML) and histone deacetylase 1 (HDAC1) to induce a decisive subset of IFN-stimulated genes (ISGs). Consequently, PLZF-deficient mice had a specific ISG expression defect and as a result were more susceptible to viral infection. This susceptibility correlated with a marked decrease in the expression of the key antiviral mediators and an impaired IFN-mediated induction of natural killer cell function. These results provide new insights into the regulatory mechanisms of IFN signaling and the induction of innate antiviral immunity.
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the Promyelocytic Leukemia Protein functions as a negative regulator of ifn γ signaling
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Younhee Choi, Pier Paolo Pandolfi, Rosa Bernardi, Etty N BenvenisteAbstract:IFN-γ is an immunomodulatory cytokine and uses the STAT-1α transcription factor to mediate gene expression. The Promyelocytic Leukemia (PML) Protein regulates transcription as an activator or repressor, depending on the gene under investigation. Herein, we examined the influence of PML on IFN-γ signaling, using PML wild-type (Pml+/+) and deficient (Pml−/−) mouse embryonic fibroblasts (MEF). Pml−/− MEF exhibit enhanced IFN-γ-induced STAT-1α transcriptional activity compared with Pml+/+ cells. Moreover, reconstitution of PML in Pml−/− MEF reduced STAT-1α transcriptional activity to levels comparable to Pml+/+ MEF. Numerous endogenous IFN-γ-regulated genes were up-regulated in Pml−/− MEF compared with Pml+/+ MEF. IFN-γ-mediated STAT-1α DNA-binding activity was enhanced in Pml−/− cells compared with Pml+/+ cells. Lastly, IFN-γ enhanced the formation of a PML–STAT-1α complex in the nucleus. These data suggest a novel function for PML in the IFN-γ signaling pathway by inhibiting STAT-1α DNA binding and transcriptional activity.
Xiwen Cheng - One of the best experts on this subject based on the ideXlab platform.
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ablation of Promyelocytic Leukemia Protein pml re patterns energy balance and protects mice from obesity induced by a western diet
Journal of Biological Chemistry, 2013Co-Authors: Xiwen Cheng, Yu Liu, Shuang Guo, Hao Chu, Parvin Hakimi, Nathan A Berger, Richard W Hanson, Hung Ying KaoAbstract:The Promyelocytic Leukemia Protein is a well known tumor suppressor, but its role in metabolism is largely unknown. Mice with a deletion in the gene for PML (KO mice) exhibit altered gene expression in liver, adipose tissue, and skeletal muscle, an accelerated rate of fatty acid metabolism, abnormal glucose metabolism, constitutive AMP-activating kinase (AMPK) activation, and insulin resistance in skeletal muscle. Last, an increased rate of energy expenditure protects PML KO mice from the effects of obesity induced by a Western diet. Collectively, our study uncovers a previously unappreciated role of PML in the regulation of metabolism and energy balance in mice.
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Promyelocytic Leukemia Protein pml regulates endothelial cell network formation and migration in response to tumor necrosis factor α tnfα and interferon α ifnα
Journal of Biological Chemistry, 2012Co-Authors: Xiwen Cheng, Yu Liu, Hao Chu, Hung Ying KaoAbstract:Promyelocytic Leukemia Protein (PML) is a tumor suppressor that is highly expressed in vascular endothelium and inflamed tissues, yet its role in inflammation-associated cytokine-regulated angiogenesis and underlying mechanism remains largely unclear. We show that tumor necrosis factor α (TNFα) and interferon α (IFNα) stimulate PML expression while suppressing EC network formation and migration, two key events during angiogenesis. By a knockdown approach, we demonstrate that PML is indispensable for TNFα- and IFNα-mediated inhibition of EC network formation. We further demonstrate that signal transducer and activator of transcription 1 (STAT1) binds PML promoter and that is an important regulator of PML expression. Knockdown of STAT1 reduces endogenous PML and blocks TNFα- and IFNα-induced PML accumulation and relieves TNFα- and IFNα-mediated inhibition of EC network formation. Our data also indicate that PML regulates EC migration, in part, by modulating expression of downstream genes, such as negatively regulating integrin β1 (ITGB1). In addition, knockdown of STAT1 or PML alleviates TNFα- and IFNα-mediated inhibition of ITGB1 expression. Antibody blockade demonstrates that ITGB1 is functionally important for PML- and STAT1-regulated EC migration. Taken together, our data provide novel mechanistic insights that PML functions as a negative regulator in EC network formation and migration.
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histone deacetylase 7 promotes pml sumoylation and is essential for pml nuclear body formation
Molecular and Cellular Biology, 2008Co-Authors: Chun Chen Ho, Erin L Reineke, Xiwen Cheng, Sharmistha Chakraborty, Kristopher J Stanya, Hsiu-ming ShihAbstract:Promyelocytic Leukemia Protein (PML) sumoylation has been proposed to control the formation of PML nuclear bodies (NBs) and is crucial for PML-dependent cellular processes, including apoptosis and transcriptional regulation. However, the regulatory mechanisms of PML sumoylation and its specific roles in the formation of PML NBs remain largely unknown. Here, we show that histone deacetylase 7 (HDAC7) knockdown reduces the size and the number of the PML NBs in human umbilical vein endothelial cells (HUVECs). HDAC7 coexpression stimulates PML sumoylation independent of its HDAC activity. Furthermore, HDAC7 associates with the E2 SUMO ligase, Ubc9, and stimulates PML sumoylation in vitro, suggesting that it possesses a SUMO E3 ligase-like activity to promote PML sumoylation. Importantly, HDAC7 knockdown inhibits tumor necrosis factor alpha-induced PML sumoylation and the formation of PML NBs in HUVECs. These results demonstrate a novel function of HDAC7 and provide a regulatory mechanism of PML sumoylation.
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signal dependent regulation of transcription by histone deacetylase 7 involves recruitment to Promyelocytic Leukemia Protein nuclear bodies
Molecular Biology of the Cell, 2008Co-Authors: Xiwen Cheng, Kun Sang ChangAbstract:Promyelocytic Leukemia Protein (PML) nuclear bodies (NBs) are dynamic subnuclear compartments that play roles in several cellular processes, including apoptosis, transcriptional regulation, and DNA repair. Histone deacetylase (HDAC) 7 is a potent corepressor that inhibits transcription by myocyte enhancer factor 2 (MEF2) transcription factors. We show here that endogenous HDAC7 and PML interact and partially colocalize in PML NBs. Tumor necrosis factor (TNF)-α treatment recruits HDAC7 to PML NBs and enhances association of HDAC7 with PML in human umbilical vein endothelial cells. Consequently, TNF-α promotes dissociation of HDAC7 from MEF2 transcription factors and the promoters of MEF2 target genes such as matrix metalloProteinase (MMP)-10, leading to accumulation of MMP-10 mRNA. Conversely, knockdown of PML enhances the association between HDAC7 and MEF2 and decreases MMP-10 mRNA accumulation. Accordingly, ectopic expression of PML recruits HDAC7 to PML NBs and leads to activation of MEF2 reporter activity. Notably, small interfering RNA knockdown of PML decreases basal and TNF-α-induced MMP-10 mRNA accumulation. Our results reveal a novel mechanism by which PML sequesters HDAC7 to relieve repression and up-regulate gene expression.
Erin L Reineke - One of the best experts on this subject based on the ideXlab platform.
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mitogen activated Protein kinase extracellular signal regulated kinase 2 phosphorylates and promotes pin1 Protein dependent Promyelocytic Leukemia Protein turnover
Journal of Biological Chemistry, 2011Co-Authors: Jun Hee Lim, Erin L Reineke, Yu Liu, Hung Ying KaoAbstract:The Promyelocytic Leukemia (PML) Protein is a tumor suppressor that has an important role in several cellular processes, including apoptosis, viral infection, DNA damage repair, cell cycle regulation, and senescence. PML is an essential component of sub-nuclear structures called PML nuclear bodies (NBs). Our laboratory has previously demonstrated that the peptidyl-prolyl cis-trans isomerase, Pin1, binds and targets PML for degradation in a phosphorylation-dependent manner. To further elucidate the mechanisms underlying Pin1-mediated PML degradation, we aimed to identify one or more factors that promote PML phosphorylation. Here we show that treatment with U0126, an inhibitor of the ERK2 upstream kinases MEK1/2, leads to an increase in PML Protein accumulation and an inhibition of the interaction between Pin1 and PML in MDA-MB-231 breast cancer cells. Consistent with this observation, phosphorylated ERK2 partially co-localized with PML NBs. Although U0126 up-regulated exogenous wild-type PML levels, it did not have an effect on the steady-state level of a mutant form of PML that is defective in binding Pin1. In addition, exogenous wild-type, but not Pin1 binding-defective PML Protein expression levels were decreased by overexpression of ERK2. In contrast, knockdown of ERK2 by siRNA resulted in an increase in PML Protein levels and an increase in the formation of PML NBs. Using phospho-specific antibodies, we identified Ser-403 and Ser-505 as the ERK2 targets that promote Pin1-mediated PML degradation. Finally, we demonstrated that EGF induced activation of ERK and interaction between PML and phosphorylated ERK resulting in a decrease in PML Protein levels. Taken together, our results support a model in which Pin1 promotes PML degradation in an ERK2-dependent manner.
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Promyelocytic Leukemia Protein controls cell migration in response to hydrogen peroxide and insulin like growth factor 1
Journal of Biological Chemistry, 2010Co-Authors: Erin L Reineke, Yu Liu, Hung Ying KaoAbstract:Promyelocytic Leukemia Protein (PML) was originally identified as part of a chromosomal translocation that contributes to the development of acute Promyelocytic Leukemia (APL). Since its discovery, PML has been found to play diverse roles in different cellular processes. Notably, PML has anti-proliferative and pro-apoptotic activity that supports its role as a tumor suppressor. We have previously shown that the peptidyl-prolyl isomerase Pin1 is able to affect cell proliferation and hydrogen peroxide (H2O2)-mediated cell death through modulation of the steady-state levels of PML. We have extended these studies to show that the interaction between PML and Pin1 is targeted by multiple extracellular signals in the cell. We show that H2O2 up-regulates and IGF-1 down-regulates PML expression in a Pin1-dependent manner. Interestingly, we found that H2O2- and IGF-1-mediated alteration in PML accumulation regulate MDA-MB-231 cell migration. Furthermore, we show that the control of cell migration by PML, and thus H2O2 and IGF-1, results from PML-dependent decreased expression of integrin β1 (ITGB1). Knockdown of Pin1 leads to decreased cell migration, lower levels of ITGB1 expression and resistance to IGF-1- and H2O2-induced changes in cell migration and ITGB1 expression. Taken together, our work identifies PML as a common target for H2O2 and IGF-1 and supports a novel tumor suppressive role for PML in controlling cell migration through the expression of ITGB1.
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targeting Promyelocytic Leukemia Protein a means to regulating pml nuclear bodies
International Journal of Biological Sciences, 2009Co-Authors: Erin L Reineke, Hung Ying KaoAbstract:The Promyelocytic Leukemia Protein (PML) is involved in many cellular processes including cell cycle progression, DNA damage response, transcriptional regulation, viral infection, and apoptosis. These cellular activities often rely on the localization of PML to unique subnuclear structures known as PML nuclear bodies (NBs). More than 50 cellular Proteins are known to traffic in and out of PML NBs, either transiently or constitutively. In order to understand the dynamics of these NBs, it is important to delineate the regulation of PML itself. PML is subject to extensive regulation at transcriptional, post-transcriptional, and post-translational levels. Many of these modes of regulation depend on the cellular context and the presence of extracellular signals. This review focuses on the current knowledge of regulation of PML under normal cellular conditions as well as the role for regulation of PML in viral infection and cancer.
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histone deacetylase 7 promotes pml sumoylation and is essential for pml nuclear body formation
Molecular and Cellular Biology, 2008Co-Authors: Chun Chen Ho, Erin L Reineke, Xiwen Cheng, Sharmistha Chakraborty, Kristopher J Stanya, Hsiu-ming ShihAbstract:Promyelocytic Leukemia Protein (PML) sumoylation has been proposed to control the formation of PML nuclear bodies (NBs) and is crucial for PML-dependent cellular processes, including apoptosis and transcriptional regulation. However, the regulatory mechanisms of PML sumoylation and its specific roles in the formation of PML NBs remain largely unknown. Here, we show that histone deacetylase 7 (HDAC7) knockdown reduces the size and the number of the PML NBs in human umbilical vein endothelial cells (HUVECs). HDAC7 coexpression stimulates PML sumoylation independent of its HDAC activity. Furthermore, HDAC7 associates with the E2 SUMO ligase, Ubc9, and stimulates PML sumoylation in vitro, suggesting that it possesses a SUMO E3 ligase-like activity to promote PML sumoylation. Importantly, HDAC7 knockdown inhibits tumor necrosis factor alpha-induced PML sumoylation and the formation of PML NBs in HUVECs. These results demonstrate a novel function of HDAC7 and provide a regulatory mechanism of PML sumoylation.
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degradation of the tumor suppressor pml by pin1 contributes to the cancer phenotype of breast cancer mda mb 231 cells
Molecular and Cellular Biology, 2008Co-Authors: Erin L Reineke, Kun Sang Chang, Kristopher J Stanya, Yu Liu, Minh Lam, Qing Liu, Anthony R Means, Hung Ying KaoAbstract:Promyelocytic Leukemia Protein (PML) is an important regulator due to its role in numerous cellular processes including apoptosis, viral infection, senescence, DNA damage repair, and cell cycle regulation. Despite the role of PML in many cellular functions, little is known about the regulation of PML itself. We show that PML stability is regulated through interaction with the peptidyl-prolyl cis-trans isomerase Pin1. This interaction is mediated through four serine-proline motifs in the C terminus of PML. Binding to Pin1 results in degradation of PML in a phosphorylation-dependent manner. Furthermore, our data indicate that sumoylation of PML blocks the interaction, thus preventing degradation of PML by this pathway. Functionally, we show that in the MDA-MB-231 breast cancer cell line modulating levels of Pin1 affects steady-state levels of PML. Furthermore, degradation of PML due to Pin1 acts both to protect these cells from hydrogen peroxide-induced death and to increase the rate of proliferation. Taken together, our work defines a novel mechanism by which sumoylation of PML prevents Pin1-dependent degradation. This interaction likely occurs in numerous cell lines and may be a pathway for oncogenic transformation.
Katherine L. B. Borden - One of the best experts on this subject based on the ideXlab platform.
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controlling gene expression through rna regulons the role of the eukaryotic translation initiation factor eif4e
Cell Cycle, 2007Co-Authors: Biljana Culjkovic, Ivan Topisirovic, Katherine L. B. BordenAbstract:The eukaryotic translation initiation factor eIF4E is a potent oncogene.1 In fact, its overexpression in human cancer often correlates with poor prognosis.1, 2 Traditionally, eIF4E plays a role in translation initiation where it binds the 5’ m7G cap found on mRNAs.3 More recent studies indicate that a significant fraction of eIF4E (up to 68%) resides in the nucleus where it regulates the nuclear export of specific mRNAs. Additionally, eIF4E may play a role in mRNA sequestration and stability in cytoplasmic processing bodies (P-bodies).4, 5 Our recent studies suggest that eIF4E governs cell cycle progression and cellular proliferation by coordinately orchestrating the expression of several genes at the post-transcriptional level. Hence, eIF4E functions as a central node of an RNA regulon (described below), which plays an essential role in normal differentiation and development and is frequently dysregulated in cancer. Several cellular factors, such as the Promyelocytic Leukemia Protein PML, modulate the fu...
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eif4e is a central node of an rna regulon that governs cellular proliferation
Journal of Cell Biology, 2006Co-Authors: Biljana Culjkovic, Ivan Topisirovic, Lucy Skrabanek, Melisa Ruizgutierrez, Katherine L. B. BordenAbstract:This study demonstrates that the eukaryotic translation initiation factor eIF4E is a critical node in an RNA regulon that impacts nearly every stage of cell cycle progression. Specifically, eIF4E coordinately promotes the messenger RNA (mRNA) export of several genes involved in the cell cycle. A common feature of these mRNAs is a structurally conserved, ∼50-nucleotide element in the 3′ untranslated region denoted as an eIF4E sensitivity element. This element is sufficient for localization of capped mRNAs to eIF4E nuclear bodies, formation of eIF4E-specific ribonucleoProteins in the nucleus, and eIF4E-dependent mRNA export. The roles of eIF4E in translation and mRNA export are distinct, as they rely on different mRNA elements. Furthermore, eIF4E-dependent mRNA export is independent of ongoing RNA or Protein synthesis. Unlike the NXF1-mediated export of bulk mRNAs, eIF4E-dependent mRNA export is CRM1 dependent. Finally, the growth-suppressive Promyelocytic Leukemia Protein (PML) inhibits this RNA regulon. These data provide novel perspectives into the proliferative and oncogenic properties of eIF4E.
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pondering the Promyelocytic Leukemia Protein pml puzzle possible functions for pml nuclear bodies
Molecular and Cellular Biology, 2002Co-Authors: Katherine L. B. BordenAbstract:It has become clear that the nucleus is organized into discrete structures. Although not membrane bound, these structures are considered nuclear organelles. Widespread interest in one such nuclear organelle, the Promyelocytic Leukemia nuclear body (NB), has emerged because of its link to several human disorders, including acute Promyelocytic Leukemia and AIDS. Studies of the physiological effects of Promyelocytic Leukemia NBs and the Promyelocytic Leukemia Protein (PML) indicate that these play roles in growth control, transformation suppression, apoptosis and Ras induced senescence. Unfortunately, the molecular and biochemical bases for physiological phenomena associated with PML are not well understood. PML and, by inference, the PML NB have been ascribed apparently disparate roles in transcription, DNA repair, DNA replication, and RNA transport. Its clear physiological importance means that defining a set of discrete biochemical functions for the PML NB is critical. This review focuses on the current theories for molecular and biochemical functions of the PML NB and the supporting evidence for each. PML NBs, also known as PML oncogenic domains, nuclear domain 10's, or Kremer bodies, are currently defined by the presence of PML at these nuclear structures. PML and its associated NBs were first described in a series of studies in the early 1990s which showed that PML was fused to the retinoic acid receptor alpha (RARα) in acute Promyelocytic Leukemia (APL) patients (reviewed in reference 63). These studies demonstrated that PML NBs were similar to those previously observed by electron microscopy in the 1960s (63). Intriguingly, NBs were disrupted in the APL patients but reformed after treatment with all-trans-retinoic acid (ATRA) (36). Reformation of bodies correlated with remission of disease in patients. This was the first evidence that the integrity of these structures may be critically important to the health of the cell (36, 63). These findings sparked widespread interest in the function of these organelles. These early studies also revealed that the PML Protein contained a set of novel zinc-binding domains, known as the RING and B-boxes. Early on, it was proposed that PML utilized these zinc fingers to directly bind DNA and thus alter gene expression. However, in the past 10 years, it has become clear that the RING and B-box domains forge Protein associations that are critical to the integrity of this multiProtein complex and subsequent physiological function(s) of this organelle (36, 40, 63). Most reported strategies for assessing PML NB function in essence are designed to answer the following questions: what nuclear structures are the bodies near to, what other macromolecules localize with the body, and what are the effects of disrupting the body? These strategies arise because the discrete biochemical functions of either PML or PML bodies are not known. The results of these strategies and their inherent limitations are discussed within this review. Further, the following considerations should be taken into account in an assessment of PML NB function. First, the expression of the PML gene is not required for viability, since PML−/− mice develop in essence normally and do not get spontaneous cancers at rates higher than do littermate controls (99). Second, the PML gene is not evolutionarily conserved among eukaryotes, being absent in Drosophila melanogaster, Saccharomyces cerevisiae, and Arabidopsis thaliana (see below). Third, unlike other nuclear organelles, there appears to be no PML bodies in Xenopus laevis. However, the disruption of these organelles apparently contributes to human disease. These features and their potential clues to PML NB function are discussed below. Because of space limitations, many topics are not discussed here. For instance, the study of viral systems has been key to our current understanding of the PML NB. However, an in-depth discussion of these contributions is beyond the scope of this review, but this topic is discussed elsewhere (25, 59, 72). Many excellent and comprehensive reviews have been written on various aspects of the physiological functions of PML and its relationship to APL (36, 40, 59, 63, 82). The present review attempts to describe current understanding of the molecular and biochemical underpinnings of PML NB function.
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the ring domains of the Promyelocytic Leukemia Protein pml and the arenaviral Protein z repress translation by directly inhibiting translation initiation factor eif4e
Journal of Molecular Biology, 2001Co-Authors: Alex Kentsis, Elizabeth Campbell J Dwyer, Jacqueline M Perez, Madhulika Sharma, Angus Chen, Katherine L. B. BordenAbstract:Abstract The Promyelocytic Leukemia Protein (PML) is a mammalian regulator of cell growth which is characteristically disrupted in acute Promyelocytic Leukemia and by a variety of viruses. PML contains a RING domain which is required for its growth-suppressive and antiviral properties. Although normally nuclear, in certain pathogenic conditions, including arenaviral infection, PML is relocated to the cytoplasm, where its functions are poorly understood. Here, we observe that PML and arenavirus Protein Z use regions around the first zinc-binding site of their respective RING domains to directly interact, with sub-micromolar affinity, with the dorsal surface of translation initiation factor eIF4E, representing a novel mode of eIF4E recognition. PML and Z profoundly reduce the affinity of eIF4E for its substrate, the 5′ 7-methyl guanosine cap of mRNA, by over 100-fold. Association with the dorsal surface of eIF4E and direct antagonism of mRNA cap binding by PML and Z lead to direct inhibition of translation. These activities of the RING domains of PML and Z do not involve ubiquitin-mediated Protein degradation, in contrast to many RINGs which have been observed to do so. Although PML and Z have well characterized physiological functions in regulation of growth and apoptosis, this work establishes the first discrete biochemical mechanism which underlies the biological activities of their RING domains. Thus, we establish PML and Z as translational repressors, with potential contributions to the pathogenesis of acute Promyelocytic Leukemia and variety of viral infections.
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role of the Promyelocytic Leukemia Protein pml in the interferon sensitivity of lymphocytic choriomeningitis virus
Journal of Virology, 2001Co-Authors: Mahmoud Djavani, Katherine L. B. Borden, Pier Paolo Pandolfi, Juan D Rodas, Igor S Lukashevich, Douglas Horejsh, Maria S. SalvatoAbstract:Lymphocytic choriomeningitis virus (LCMV) induces type I interferon (alpha and beta interferon [IFN-α and IFN-β]) upon infection and yet is sensitive to the addition of type II interferon (gamma interferon [IFN-γ]) to the culture media. This sensitivity is biologically important because it correlates inversely with the ability of certain LCMV strains to persist in mice (D. Moskophidis, M. Battegay, M. A. Bruendler, E. Laine, I. Gresser, and R. M. Zinkernagel, J. Virol. 68:1951-1955, 1994). The cellular oncoProtein PML is induced by both IFN-α/β and IFN-γ, and PML binds the LCMV Z Protein and becomes redistributed within cells from nucleus to cytoplasm upon LCMV infection. In the present study, increased PML expression results in diminished LCMV replication, implicating PML in the IFN sensitivity of LCMV. Virus production in PML −/− murine embryonic fibroblasts (MEF) exceeds virus production in PML +/+ MEF, and this difference is exacerbated by IFN treatment that upregulates PML expression. IFN-γ also diminishes LCMV production in PML −/− cells; therefore, viral IFN sensitivity is not entirely due to PML. Both viral mRNA production and viral Protein production decrease as PML expression increases. Here we propose that PML reduces LCMV transcription through its interaction with the Z Protein.
