The Experts below are selected from a list of 14844 Experts worldwide ranked by ideXlab platform
Richard S Jope - One of the best experts on this subject based on the ideXlab platform.
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central role of glycogen synthase kinase 3β in endoplasmic reticulum stress induced caspase 3 activation
Journal of Biological Chemistry, 2002Co-Authors: Ling Song, Patrizia De Sarno, Richard S JopeAbstract:Stress of the endoplasmic reticulum (ER), which is associated with many neurodegenerative conditions, can lead to the elimination of affected cells by apoptosis through only partially understood mechanisms. Thapsigargin, which causes ER stress by inhibiting the ER Ca(2+)-ATPase, was found to not only activate the apoptosis effector caspase-3 but also to cause a large and prolonged increase in the activity of glycogen synthase kinase-3beta (GSK3beta). Activation of GSK3beta was obligatory for Thapsigargin-induced activation of caspase-3, because inhibition of GSK3beta by expression of dominant-negative GSK3beta or by the GSK3beta inhibitor lithium blocked caspase-3 activation. Thapsigargin treatment activated GSK3beta by inducing dephosphorylation of phospho-Ser-9 of GSK3beta, a phosphorylation that normally maintains GSK3beta inactivated. Caspase-3 activation induced by Thapsigargin was blocked by increasing the phosphorylation of Ser-9-GSK3beta with insulin-like growth factor-1 or with the phosphatase inhibitors okadaic acid and calyculin A, but the calcineurin inhibitors FK506 and cyclosporin A were ineffective. Insulin-like growth factor-1, okadaic acid, calyculin A, and lithium also protected cells from two other inducers of ER stress, tunicamycin and brefeldin A. Thus, ER stress activates GSK3beta through dephosphorylation of phospho-Ser-9, a prerequisite for caspase-3 activation, and this process is amenable to pharmacological intervention.
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central role of glycogen synthase kinase 3β in endoplasmic reticulum stress induced caspase 3 activation
Journal of Biological Chemistry, 2002Co-Authors: Ling Song, Patrizia De Sarno, Richard S JopeAbstract:Abstract Stress of the endoplasmic reticulum (ER), which is associated with many neurodegenerative conditions, can lead to the elimination of affected cells by apoptosis through only partially understood mechanisms. Thapsigargin, which causes ER stress by inhibiting the ER Ca2+-ATPase, was found to not only activate the apoptosis effector caspase-3 but also to cause a large and prolonged increase in the activity of glycogen synthase kinase-3β (GSK3β). Activation of GSK3β was obligatory for Thapsigargin-induced activation of caspase-3, because inhibition of GSK3β by expression of dominant-negative GSK3β or by the GSK3β inhibitor lithium blocked caspase-3 activation. Thapsigargin treatment activated GSK3β by inducing dephosphorylation of phospho-Ser-9 of GSK3β, a phosphorylation that normally maintains GSK3β inactivated. Caspase-3 activation induced by Thapsigargin was blocked by increasing the phosphorylation of Ser-9-GSK3β with insulin-like growth factor-1 or with the phosphatase inhibitors okadaic acid and calyculin A, but the calcineurin inhibitors FK506 and cyclosporin A were ineffective. Insulin-like growth factor-1, okadaic acid, calyculin A, and lithium also protected cells from two other inducers of ER stress, tunicamycin and brefeldin A. Thus, ER stress activates GSK3β through dephosphorylation of phospho-Ser-9, a prerequisite for caspase-3 activation, and this process is amenable to pharmacological intervention.
James S K Sham - One of the best experts on this subject based on the ideXlab platform.
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chronic hypoxia induced upregulation of store operated and receptor operated ca2 channels in pulmonary arterial smooth muscle cells a novel mechanism of hypoxic pulmonary hypertension
Circulation Research, 2004Co-Authors: George P H Leung, Wei Min Zhang, Xiaoru Yang, James S K ShamAbstract:Chronic hypoxic pulmonary hypertension is associated with profound vascular remodeling and alterations in Ca 2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Recent studies show that transient receptor potential (TRPC) genes, which encode store-operated and receptor-operated cation channels, play important roles in Ca 2+ regulation and cell proliferation. However, the influence of chronic hypoxia on TRPC channels has not been determined. Here we compared TRPC expression, and store- and receptor-operated Ca 2+ entries in PASMCs of normoxic and chronic hypoxic rats. Reverse-transcription polymerase chain reaction (RT-PCR), Western blot, and immunostaining showed consistently that TRPC1, TRPC3, and TRPC6 were expressed in intralobar pulmonary arteries (PAs) and PASMCs. Application of 1-oleoyl-2-acetyl-sn-glycerol (OAG) to directly activate receptor-operated channels, or Thapsigargin to deplete Ca 2+ stores, caused dramatic increase in cation entry measured by Mn 2+ quenching of fura-2 and by Ca 2+ transients. OAG-induced responses were ≈700-fold more resistant to La 3+ inhibition than Thapsigargin-induced responses. siRNA knockdown of TRPC1 and TRPC6 specifically attenuated Thapsigargin- and OAG-induced cation entries, respectively, indicating that TRPC1 mediates store-operated entry and TRPC6 mediates receptor-operated entry. In hypoxic PAs, there were 2- to 3-fold increases in TRPC1 and TRPC6 expression. They were accompanied by significant increases in basal, OAG-induced, and Thapsigargin-induced cation entries in hypoxic PASMCs. Moreover, removal of Ca 2+ or inhibition of store-operated Ca 2+ entry with La 3+ and SK&F-96365 reversed the elevated basal [Ca 2+ ] i in PASMCs and vascular tone in PAs of chronic hypoxic animals, but nifedipine had minimal effects. Our results for the first time to our knowledge show that both store- and receptor-operated channels of PASMCs are upregulated by chronic hypoxia and contribute to the enhanced vascular tone in hypoxic pulmonary hypertension.
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chronic hypoxia induced upregulation of store operated and receptor operated ca2 channels in pulmonary arterial smooth muscle cells a novel mechanism of hypoxic pulmonary hypertension
Circulation Research, 2004Co-Authors: Mo Jun Lin, George P H Leung, Wei Min Zhang, Xiaoru Yang, Kaypong Yip, Chung Ming Tse, James S K ShamAbstract:Chronic hypoxic pulmonary hypertension is associated with profound vascular remodeling and alterations in Ca(2+) homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Recent studies show that transient receptor potential (TRPC) genes, which encode store-operated and receptor-operated cation channels, play important roles in Ca(2+) regulation and cell proliferation. However, the influence of chronic hypoxia on TRPC channels has not been determined. Here we compared TRPC expression, and store- and receptor-operated Ca(2+) entries in PASMCs of normoxic and chronic hypoxic rats. Reverse-transcription polymerase chain reaction (RT-PCR), Western blot, and immunostaining showed consistently that TRPC1, TRPC3, and TRPC6 were expressed in intralobar pulmonary arteries (PAs) and PASMCs. Application of 1-oleoyl-2-acetyl-sn-glycerol (OAG) to directly activate receptor-operated channels, or Thapsigargin to deplete Ca(2+) stores, caused dramatic increase in cation entry measured by Mn(2+) quenching of fura-2 and by Ca(2+) transients. OAG-induced responses were approximately 700-fold more resistant to La(3+) inhibition than Thapsigargin-induced responses. siRNA knockdown of TRPC1 and TRPC6 specifically attenuated Thapsigargin- and OAG-induced cation entries, respectively, indicating that TRPC1 mediates store-operated entry and TRPC6 mediates receptor-operated entry. In hypoxic PAs, there were 2- to 3-fold increases in TRPC1 and TRPC6 expression. They were accompanied by significant increases in basal, OAG-induced, and Thapsigargin-induced cation entries in hypoxic PASMCs. Moreover, removal of Ca(2+) or inhibition of store-operated Ca(2+) entry with La(3+) and SK&F-96365 reversed the elevated basal [Ca(2+)](i) in PASMCs and vascular tone in PAs of chronic hypoxic animals, but nifedipine had minimal effects. Our results for the first time to our knowledge show that both store- and receptor-operated channels of PASMCs are upregulated by chronic hypoxia and contribute to the enhanced vascular tone in hypoxic pulmonary hypertension.
Ling Song - One of the best experts on this subject based on the ideXlab platform.
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central role of glycogen synthase kinase 3β in endoplasmic reticulum stress induced caspase 3 activation
Journal of Biological Chemistry, 2002Co-Authors: Ling Song, Patrizia De Sarno, Richard S JopeAbstract:Stress of the endoplasmic reticulum (ER), which is associated with many neurodegenerative conditions, can lead to the elimination of affected cells by apoptosis through only partially understood mechanisms. Thapsigargin, which causes ER stress by inhibiting the ER Ca(2+)-ATPase, was found to not only activate the apoptosis effector caspase-3 but also to cause a large and prolonged increase in the activity of glycogen synthase kinase-3beta (GSK3beta). Activation of GSK3beta was obligatory for Thapsigargin-induced activation of caspase-3, because inhibition of GSK3beta by expression of dominant-negative GSK3beta or by the GSK3beta inhibitor lithium blocked caspase-3 activation. Thapsigargin treatment activated GSK3beta by inducing dephosphorylation of phospho-Ser-9 of GSK3beta, a phosphorylation that normally maintains GSK3beta inactivated. Caspase-3 activation induced by Thapsigargin was blocked by increasing the phosphorylation of Ser-9-GSK3beta with insulin-like growth factor-1 or with the phosphatase inhibitors okadaic acid and calyculin A, but the calcineurin inhibitors FK506 and cyclosporin A were ineffective. Insulin-like growth factor-1, okadaic acid, calyculin A, and lithium also protected cells from two other inducers of ER stress, tunicamycin and brefeldin A. Thus, ER stress activates GSK3beta through dephosphorylation of phospho-Ser-9, a prerequisite for caspase-3 activation, and this process is amenable to pharmacological intervention.
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central role of glycogen synthase kinase 3β in endoplasmic reticulum stress induced caspase 3 activation
Journal of Biological Chemistry, 2002Co-Authors: Ling Song, Patrizia De Sarno, Richard S JopeAbstract:Abstract Stress of the endoplasmic reticulum (ER), which is associated with many neurodegenerative conditions, can lead to the elimination of affected cells by apoptosis through only partially understood mechanisms. Thapsigargin, which causes ER stress by inhibiting the ER Ca2+-ATPase, was found to not only activate the apoptosis effector caspase-3 but also to cause a large and prolonged increase in the activity of glycogen synthase kinase-3β (GSK3β). Activation of GSK3β was obligatory for Thapsigargin-induced activation of caspase-3, because inhibition of GSK3β by expression of dominant-negative GSK3β or by the GSK3β inhibitor lithium blocked caspase-3 activation. Thapsigargin treatment activated GSK3β by inducing dephosphorylation of phospho-Ser-9 of GSK3β, a phosphorylation that normally maintains GSK3β inactivated. Caspase-3 activation induced by Thapsigargin was blocked by increasing the phosphorylation of Ser-9-GSK3β with insulin-like growth factor-1 or with the phosphatase inhibitors okadaic acid and calyculin A, but the calcineurin inhibitors FK506 and cyclosporin A were ineffective. Insulin-like growth factor-1, okadaic acid, calyculin A, and lithium also protected cells from two other inducers of ER stress, tunicamycin and brefeldin A. Thus, ER stress activates GSK3β through dephosphorylation of phospho-Ser-9, a prerequisite for caspase-3 activation, and this process is amenable to pharmacological intervention.
George P H Leung - One of the best experts on this subject based on the ideXlab platform.
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chronic hypoxia induced upregulation of store operated and receptor operated ca2 channels in pulmonary arterial smooth muscle cells a novel mechanism of hypoxic pulmonary hypertension
Circulation Research, 2004Co-Authors: George P H Leung, Wei Min Zhang, Xiaoru Yang, James S K ShamAbstract:Chronic hypoxic pulmonary hypertension is associated with profound vascular remodeling and alterations in Ca 2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Recent studies show that transient receptor potential (TRPC) genes, which encode store-operated and receptor-operated cation channels, play important roles in Ca 2+ regulation and cell proliferation. However, the influence of chronic hypoxia on TRPC channels has not been determined. Here we compared TRPC expression, and store- and receptor-operated Ca 2+ entries in PASMCs of normoxic and chronic hypoxic rats. Reverse-transcription polymerase chain reaction (RT-PCR), Western blot, and immunostaining showed consistently that TRPC1, TRPC3, and TRPC6 were expressed in intralobar pulmonary arteries (PAs) and PASMCs. Application of 1-oleoyl-2-acetyl-sn-glycerol (OAG) to directly activate receptor-operated channels, or Thapsigargin to deplete Ca 2+ stores, caused dramatic increase in cation entry measured by Mn 2+ quenching of fura-2 and by Ca 2+ transients. OAG-induced responses were ≈700-fold more resistant to La 3+ inhibition than Thapsigargin-induced responses. siRNA knockdown of TRPC1 and TRPC6 specifically attenuated Thapsigargin- and OAG-induced cation entries, respectively, indicating that TRPC1 mediates store-operated entry and TRPC6 mediates receptor-operated entry. In hypoxic PAs, there were 2- to 3-fold increases in TRPC1 and TRPC6 expression. They were accompanied by significant increases in basal, OAG-induced, and Thapsigargin-induced cation entries in hypoxic PASMCs. Moreover, removal of Ca 2+ or inhibition of store-operated Ca 2+ entry with La 3+ and SK&F-96365 reversed the elevated basal [Ca 2+ ] i in PASMCs and vascular tone in PAs of chronic hypoxic animals, but nifedipine had minimal effects. Our results for the first time to our knowledge show that both store- and receptor-operated channels of PASMCs are upregulated by chronic hypoxia and contribute to the enhanced vascular tone in hypoxic pulmonary hypertension.
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chronic hypoxia induced upregulation of store operated and receptor operated ca2 channels in pulmonary arterial smooth muscle cells a novel mechanism of hypoxic pulmonary hypertension
Circulation Research, 2004Co-Authors: Mo Jun Lin, George P H Leung, Wei Min Zhang, Xiaoru Yang, Kaypong Yip, Chung Ming Tse, James S K ShamAbstract:Chronic hypoxic pulmonary hypertension is associated with profound vascular remodeling and alterations in Ca(2+) homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Recent studies show that transient receptor potential (TRPC) genes, which encode store-operated and receptor-operated cation channels, play important roles in Ca(2+) regulation and cell proliferation. However, the influence of chronic hypoxia on TRPC channels has not been determined. Here we compared TRPC expression, and store- and receptor-operated Ca(2+) entries in PASMCs of normoxic and chronic hypoxic rats. Reverse-transcription polymerase chain reaction (RT-PCR), Western blot, and immunostaining showed consistently that TRPC1, TRPC3, and TRPC6 were expressed in intralobar pulmonary arteries (PAs) and PASMCs. Application of 1-oleoyl-2-acetyl-sn-glycerol (OAG) to directly activate receptor-operated channels, or Thapsigargin to deplete Ca(2+) stores, caused dramatic increase in cation entry measured by Mn(2+) quenching of fura-2 and by Ca(2+) transients. OAG-induced responses were approximately 700-fold more resistant to La(3+) inhibition than Thapsigargin-induced responses. siRNA knockdown of TRPC1 and TRPC6 specifically attenuated Thapsigargin- and OAG-induced cation entries, respectively, indicating that TRPC1 mediates store-operated entry and TRPC6 mediates receptor-operated entry. In hypoxic PAs, there were 2- to 3-fold increases in TRPC1 and TRPC6 expression. They were accompanied by significant increases in basal, OAG-induced, and Thapsigargin-induced cation entries in hypoxic PASMCs. Moreover, removal of Ca(2+) or inhibition of store-operated Ca(2+) entry with La(3+) and SK&F-96365 reversed the elevated basal [Ca(2+)](i) in PASMCs and vascular tone in PAs of chronic hypoxic animals, but nifedipine had minimal effects. Our results for the first time to our knowledge show that both store- and receptor-operated channels of PASMCs are upregulated by chronic hypoxia and contribute to the enhanced vascular tone in hypoxic pulmonary hypertension.
Patrizia De Sarno - One of the best experts on this subject based on the ideXlab platform.
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central role of glycogen synthase kinase 3β in endoplasmic reticulum stress induced caspase 3 activation
Journal of Biological Chemistry, 2002Co-Authors: Ling Song, Patrizia De Sarno, Richard S JopeAbstract:Stress of the endoplasmic reticulum (ER), which is associated with many neurodegenerative conditions, can lead to the elimination of affected cells by apoptosis through only partially understood mechanisms. Thapsigargin, which causes ER stress by inhibiting the ER Ca(2+)-ATPase, was found to not only activate the apoptosis effector caspase-3 but also to cause a large and prolonged increase in the activity of glycogen synthase kinase-3beta (GSK3beta). Activation of GSK3beta was obligatory for Thapsigargin-induced activation of caspase-3, because inhibition of GSK3beta by expression of dominant-negative GSK3beta or by the GSK3beta inhibitor lithium blocked caspase-3 activation. Thapsigargin treatment activated GSK3beta by inducing dephosphorylation of phospho-Ser-9 of GSK3beta, a phosphorylation that normally maintains GSK3beta inactivated. Caspase-3 activation induced by Thapsigargin was blocked by increasing the phosphorylation of Ser-9-GSK3beta with insulin-like growth factor-1 or with the phosphatase inhibitors okadaic acid and calyculin A, but the calcineurin inhibitors FK506 and cyclosporin A were ineffective. Insulin-like growth factor-1, okadaic acid, calyculin A, and lithium also protected cells from two other inducers of ER stress, tunicamycin and brefeldin A. Thus, ER stress activates GSK3beta through dephosphorylation of phospho-Ser-9, a prerequisite for caspase-3 activation, and this process is amenable to pharmacological intervention.
-
central role of glycogen synthase kinase 3β in endoplasmic reticulum stress induced caspase 3 activation
Journal of Biological Chemistry, 2002Co-Authors: Ling Song, Patrizia De Sarno, Richard S JopeAbstract:Abstract Stress of the endoplasmic reticulum (ER), which is associated with many neurodegenerative conditions, can lead to the elimination of affected cells by apoptosis through only partially understood mechanisms. Thapsigargin, which causes ER stress by inhibiting the ER Ca2+-ATPase, was found to not only activate the apoptosis effector caspase-3 but also to cause a large and prolonged increase in the activity of glycogen synthase kinase-3β (GSK3β). Activation of GSK3β was obligatory for Thapsigargin-induced activation of caspase-3, because inhibition of GSK3β by expression of dominant-negative GSK3β or by the GSK3β inhibitor lithium blocked caspase-3 activation. Thapsigargin treatment activated GSK3β by inducing dephosphorylation of phospho-Ser-9 of GSK3β, a phosphorylation that normally maintains GSK3β inactivated. Caspase-3 activation induced by Thapsigargin was blocked by increasing the phosphorylation of Ser-9-GSK3β with insulin-like growth factor-1 or with the phosphatase inhibitors okadaic acid and calyculin A, but the calcineurin inhibitors FK506 and cyclosporin A were ineffective. Insulin-like growth factor-1, okadaic acid, calyculin A, and lithium also protected cells from two other inducers of ER stress, tunicamycin and brefeldin A. Thus, ER stress activates GSK3β through dephosphorylation of phospho-Ser-9, a prerequisite for caspase-3 activation, and this process is amenable to pharmacological intervention.
