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Sarah Spiegel - One of the best experts on this subject based on the ideXlab platform.
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n n dimethylsphingosine is a potent Competitive Inhibitor of sphingosine kinase but not of protein kinase c modulation of cellular levels of sphingosine 1 phosphate and ceramide
Biochemistry, 1998Co-Authors: Lisa C Edsall, James R Van Brocklyn, Olivier Cuvillier, And Burkhard Kleuser, Sarah SpiegelAbstract:Sphingosine 1-phosphate (SPP), a lipid second messenger formed by the action of sphingosine kinase, has been implicated in regulating diverse biological processes, including growth, survival, and differentiation. N,N-Dimethylsphingosine (DMS) inhibits sphingosine kinase and has been used to investigate the biological roles of SPP; however, little is known of the mechanism of inhibition of sphingosine kinase by DMS. In addition, DMS has been shown to inhibit protein kinase C in vitro. Here we report that DMS is a Competitive Inhibitor of sphingosine kinase from U937 monoblastic leukemia cells, Swiss 3T3 fibroblasts, and PC12 pheochromocytoma cells. DMS decreases basal levels of SPP and prevents increases in SPP in response to physiological stimuli known to activate sphingosine kinase. DMS also effectively increases cellular levels of ceramide in a variety of cell types, and resetting of the ceramide/SPP rheostat may account for the pro-apoptotic effects of DMS. Moreover, DMS, at concentrations which effectively inhibit sphingosine kinase, has no effect on protein kinase C activity or its membrane translocation. Thus, DMS acts as a specific Competitive Inhibitor of sphingosine kinase in diverse cell types and is a useful tool to elucidate the role of SPP as an intracellular second messenger.
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n n dimethylsphingosine is a potent Competitive Inhibitor of sphingosine kinase but not of protein kinase c modulation of cellular levels of sphingosine 1 phosphate and ceramide
Biochemistry, 1998Co-Authors: Lisa C Edsall, Olivier Cuvillier, And Burkhard Kleuser, James R Van Brocklyn, Sarah SpiegelAbstract:Sphingosine 1-phosphate (SPP), a lipid second messenger formed by the action of sphingosine kinase, has been implicated in regulating diverse biological processes, including growth, survival, and differentiation. N,N-Dimethylsphingosine (DMS) inhibits sphingosine kinase and has been used to investigate the biological roles of SPP; however, little is known of the mechanism of inhibition of sphingosine kinase by DMS. In addition, DMS has been shown to inhibit protein kinase C in vitro. Here we report that DMS is a Competitive Inhibitor of sphingosine kinase from U937 monoblastic leukemia cells, Swiss 3T3 fibroblasts, and PC12 pheochromocytoma cells. DMS decreases basal levels of SPP and prevents increases in SPP in response to physiological stimuli known to activate sphingosine kinase. DMS also effectively increases cellular levels of ceramide in a variety of cell types, and resetting of the ceramide/SPP rheostat may account for the pro-apoptotic effects of DMS. Moreover, DMS, at concentrations which effect...
Lisa C Edsall - One of the best experts on this subject based on the ideXlab platform.
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n n dimethylsphingosine is a potent Competitive Inhibitor of sphingosine kinase but not of protein kinase c modulation of cellular levels of sphingosine 1 phosphate and ceramide
Biochemistry, 1998Co-Authors: Lisa C Edsall, James R Van Brocklyn, Olivier Cuvillier, And Burkhard Kleuser, Sarah SpiegelAbstract:Sphingosine 1-phosphate (SPP), a lipid second messenger formed by the action of sphingosine kinase, has been implicated in regulating diverse biological processes, including growth, survival, and differentiation. N,N-Dimethylsphingosine (DMS) inhibits sphingosine kinase and has been used to investigate the biological roles of SPP; however, little is known of the mechanism of inhibition of sphingosine kinase by DMS. In addition, DMS has been shown to inhibit protein kinase C in vitro. Here we report that DMS is a Competitive Inhibitor of sphingosine kinase from U937 monoblastic leukemia cells, Swiss 3T3 fibroblasts, and PC12 pheochromocytoma cells. DMS decreases basal levels of SPP and prevents increases in SPP in response to physiological stimuli known to activate sphingosine kinase. DMS also effectively increases cellular levels of ceramide in a variety of cell types, and resetting of the ceramide/SPP rheostat may account for the pro-apoptotic effects of DMS. Moreover, DMS, at concentrations which effectively inhibit sphingosine kinase, has no effect on protein kinase C activity or its membrane translocation. Thus, DMS acts as a specific Competitive Inhibitor of sphingosine kinase in diverse cell types and is a useful tool to elucidate the role of SPP as an intracellular second messenger.
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n n dimethylsphingosine is a potent Competitive Inhibitor of sphingosine kinase but not of protein kinase c modulation of cellular levels of sphingosine 1 phosphate and ceramide
Biochemistry, 1998Co-Authors: Lisa C Edsall, Olivier Cuvillier, And Burkhard Kleuser, James R Van Brocklyn, Sarah SpiegelAbstract:Sphingosine 1-phosphate (SPP), a lipid second messenger formed by the action of sphingosine kinase, has been implicated in regulating diverse biological processes, including growth, survival, and differentiation. N,N-Dimethylsphingosine (DMS) inhibits sphingosine kinase and has been used to investigate the biological roles of SPP; however, little is known of the mechanism of inhibition of sphingosine kinase by DMS. In addition, DMS has been shown to inhibit protein kinase C in vitro. Here we report that DMS is a Competitive Inhibitor of sphingosine kinase from U937 monoblastic leukemia cells, Swiss 3T3 fibroblasts, and PC12 pheochromocytoma cells. DMS decreases basal levels of SPP and prevents increases in SPP in response to physiological stimuli known to activate sphingosine kinase. DMS also effectively increases cellular levels of ceramide in a variety of cell types, and resetting of the ceramide/SPP rheostat may account for the pro-apoptotic effects of DMS. Moreover, DMS, at concentrations which effect...
B L Neubauer - One of the best experts on this subject based on the ideXlab platform.
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Kinetic analysis of LY320236: Competitive Inhibitor of type I and non-Competitive Inhibitor of type II human steroid 5α-reductase
The Journal of Steroid Biochemistry and Molecular Biology, 2000Co-Authors: A M Mcnulty, J E Audia, K G Bemis, R L Goode, V P Rocco, B L NeubauerAbstract:Abstract Type I and type II steroid 5α-reductases (5α-R) catalyze the conversion of testosterone (T) to dihydrotestosterone (DHT). LY320236 is a benzoquinolinone (BQ) that inhibits 5α-R activity in human scalp skin ( Ki type I =28.7±1.87 nM) and prostatic homogenates ( Ki type II =10.6±4.5 nM). Lineweaver–Burk, Dixon, and non-linear analysis methods were used to evaluate the kinetics of 5α-R inhibition by LY320236. Non-linear modeling of experimental data evaluated V max in the presence or absence of LY320236. Experimental data modeled to the following equation 1 v = In0c+ Km/ S V max Ki I + 1 V max 1+ Km S fixing the In0c value equal to 1.0 or 0 are consistent with non-Competitive or Competitive inhibition, respectively. LY320236 is a Competitive Inhibitor of type I 5α-R ( In0c =0, Ki =3.39±0.38, RMSE = 1.300) and a non-Competitive Inhibitor of type II 5α-R ( In0c =1, Ki =29.7±3.4, RMSE = 0.0592). These data are in agreement with linear transformation of the data using Lineweaver–Burk and Dixon analyses. These enzyme kinetic data support the contention that the BQ LY320236 is a potent dual Inhibitor with differing modes of activity against the two known human 5α-reductase isozymes. LY320236 represents a class of non-steroidal 5α-R Inhibitors with potential therapeutic utility in treating a variety of androgen dependent disorders.
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Kinetic analysis of LY320236: Competitive Inhibitor of type I and non-Competitive Inhibitor of type II human steroid 5alpha-reductase.
The Journal of steroid biochemistry and molecular biology, 2000Co-Authors: A M Mcnulty, J E Audia, K G Bemis, R L Goode, V P Rocco, B L NeubauerAbstract:Type I and type II steroid 5alpha-reductases (5alpha-R) catalyze the conversion of testosterone (T) to dihydrotestosterone (DHT). LY320236 is a benzoquinolinone (BQ) that inhibits 5alpha-R activity in human scalp skin (Ki(typeI)=28.7+/-1.87 nM) and prostatic homogenates (Ki(typeII)=10.6+/-4.5 nM). Lineweaver-Burk, Dixon, and non-linear analysis methods were used to evaluate the kinetics of 5alpha-R inhibition by LY320236. Non-linear modeling of experimental data evaluated V(max) in the presence or absence of LY320236. Experimental data modeled to the following equation 1v=+ fixing the In0c value equal to 1.0 or 0 are consistent with non-Competitive or Competitive inhibition, respectively. LY320236 is a Competitive Inhibitor of type I 5alpha-R (In0c=0, Ki=3.39+/-0.38, RMSE = 1.300) and a non-Competitive Inhibitor of type II 5alpha-R (In0c=1, Ki=29. 7+/-3.4, RMSE = 0.0592). These data are in agreement with linear transformation of the data using Lineweaver-Burk and Dixon analyses. These enzyme kinetic data support the contention that the BQ LY320236 is a potent dual Inhibitor with differing modes of activity against the two known human 5alpha-reductase isozymes. LY320236 represents a class of non-steroidal 5alpha-R Inhibitors with potential therapeutic utility in treating a variety of androgen dependent disorders.
And Burkhard Kleuser - One of the best experts on this subject based on the ideXlab platform.
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n n dimethylsphingosine is a potent Competitive Inhibitor of sphingosine kinase but not of protein kinase c modulation of cellular levels of sphingosine 1 phosphate and ceramide
Biochemistry, 1998Co-Authors: Lisa C Edsall, James R Van Brocklyn, Olivier Cuvillier, And Burkhard Kleuser, Sarah SpiegelAbstract:Sphingosine 1-phosphate (SPP), a lipid second messenger formed by the action of sphingosine kinase, has been implicated in regulating diverse biological processes, including growth, survival, and differentiation. N,N-Dimethylsphingosine (DMS) inhibits sphingosine kinase and has been used to investigate the biological roles of SPP; however, little is known of the mechanism of inhibition of sphingosine kinase by DMS. In addition, DMS has been shown to inhibit protein kinase C in vitro. Here we report that DMS is a Competitive Inhibitor of sphingosine kinase from U937 monoblastic leukemia cells, Swiss 3T3 fibroblasts, and PC12 pheochromocytoma cells. DMS decreases basal levels of SPP and prevents increases in SPP in response to physiological stimuli known to activate sphingosine kinase. DMS also effectively increases cellular levels of ceramide in a variety of cell types, and resetting of the ceramide/SPP rheostat may account for the pro-apoptotic effects of DMS. Moreover, DMS, at concentrations which effectively inhibit sphingosine kinase, has no effect on protein kinase C activity or its membrane translocation. Thus, DMS acts as a specific Competitive Inhibitor of sphingosine kinase in diverse cell types and is a useful tool to elucidate the role of SPP as an intracellular second messenger.
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n n dimethylsphingosine is a potent Competitive Inhibitor of sphingosine kinase but not of protein kinase c modulation of cellular levels of sphingosine 1 phosphate and ceramide
Biochemistry, 1998Co-Authors: Lisa C Edsall, Olivier Cuvillier, And Burkhard Kleuser, James R Van Brocklyn, Sarah SpiegelAbstract:Sphingosine 1-phosphate (SPP), a lipid second messenger formed by the action of sphingosine kinase, has been implicated in regulating diverse biological processes, including growth, survival, and differentiation. N,N-Dimethylsphingosine (DMS) inhibits sphingosine kinase and has been used to investigate the biological roles of SPP; however, little is known of the mechanism of inhibition of sphingosine kinase by DMS. In addition, DMS has been shown to inhibit protein kinase C in vitro. Here we report that DMS is a Competitive Inhibitor of sphingosine kinase from U937 monoblastic leukemia cells, Swiss 3T3 fibroblasts, and PC12 pheochromocytoma cells. DMS decreases basal levels of SPP and prevents increases in SPP in response to physiological stimuli known to activate sphingosine kinase. DMS also effectively increases cellular levels of ceramide in a variety of cell types, and resetting of the ceramide/SPP rheostat may account for the pro-apoptotic effects of DMS. Moreover, DMS, at concentrations which effect...
Olivier Cuvillier - One of the best experts on this subject based on the ideXlab platform.
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n n dimethylsphingosine is a potent Competitive Inhibitor of sphingosine kinase but not of protein kinase c modulation of cellular levels of sphingosine 1 phosphate and ceramide
Biochemistry, 1998Co-Authors: Lisa C Edsall, James R Van Brocklyn, Olivier Cuvillier, And Burkhard Kleuser, Sarah SpiegelAbstract:Sphingosine 1-phosphate (SPP), a lipid second messenger formed by the action of sphingosine kinase, has been implicated in regulating diverse biological processes, including growth, survival, and differentiation. N,N-Dimethylsphingosine (DMS) inhibits sphingosine kinase and has been used to investigate the biological roles of SPP; however, little is known of the mechanism of inhibition of sphingosine kinase by DMS. In addition, DMS has been shown to inhibit protein kinase C in vitro. Here we report that DMS is a Competitive Inhibitor of sphingosine kinase from U937 monoblastic leukemia cells, Swiss 3T3 fibroblasts, and PC12 pheochromocytoma cells. DMS decreases basal levels of SPP and prevents increases in SPP in response to physiological stimuli known to activate sphingosine kinase. DMS also effectively increases cellular levels of ceramide in a variety of cell types, and resetting of the ceramide/SPP rheostat may account for the pro-apoptotic effects of DMS. Moreover, DMS, at concentrations which effectively inhibit sphingosine kinase, has no effect on protein kinase C activity or its membrane translocation. Thus, DMS acts as a specific Competitive Inhibitor of sphingosine kinase in diverse cell types and is a useful tool to elucidate the role of SPP as an intracellular second messenger.
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n n dimethylsphingosine is a potent Competitive Inhibitor of sphingosine kinase but not of protein kinase c modulation of cellular levels of sphingosine 1 phosphate and ceramide
Biochemistry, 1998Co-Authors: Lisa C Edsall, Olivier Cuvillier, And Burkhard Kleuser, James R Van Brocklyn, Sarah SpiegelAbstract:Sphingosine 1-phosphate (SPP), a lipid second messenger formed by the action of sphingosine kinase, has been implicated in regulating diverse biological processes, including growth, survival, and differentiation. N,N-Dimethylsphingosine (DMS) inhibits sphingosine kinase and has been used to investigate the biological roles of SPP; however, little is known of the mechanism of inhibition of sphingosine kinase by DMS. In addition, DMS has been shown to inhibit protein kinase C in vitro. Here we report that DMS is a Competitive Inhibitor of sphingosine kinase from U937 monoblastic leukemia cells, Swiss 3T3 fibroblasts, and PC12 pheochromocytoma cells. DMS decreases basal levels of SPP and prevents increases in SPP in response to physiological stimuli known to activate sphingosine kinase. DMS also effectively increases cellular levels of ceramide in a variety of cell types, and resetting of the ceramide/SPP rheostat may account for the pro-apoptotic effects of DMS. Moreover, DMS, at concentrations which effect...