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Carmelo Bernabeu - One of the best experts on this subject based on the ideXlab platform.

  • endoglin increases enos expression by modulating Smad2 Protein levels and Smad2 dependent tgf β signaling
    Journal of Cellular Physiology, 2007
    Co-Authors: Jose M Lopeznovoa, Ainhoa Letamendia, Fernando Perezbarriocanal, Marta Saura, Juan F. Santibanez, Liliana Attisano, Calvin P.h. Vary, Cristoforo Silvestri, Carmelo Bernabeu
    Abstract:

    The endothelial nitric oxide synthase (eNOS) is a critical regulator of cardiovascular homeostasis, whose dysregulation leads to different vascular pathologies. Endoglin is a component of the transforming growth factor beta (TGF-β) receptor complex present in endothelial cells that is involved in angiogenesis, cardiovascular development, and vascular homeostasis. Haploinsufficient expression of endoglin has been shown to downregulate endothelium-derived nitric oxide in endoglin+/− (Eng+/−) mice and cultured endothelial cells. Here, we find that TGF-β1 leads to an increased vasodilatation in Eng+/+ mice that is severely impaired in Eng+/− mice, suggesting the involvement of endoglin in the TGF-β regulated vascular homeostasis. The endoglin-dependent induction of eNOS occurs at the transcriptional level and is mediated by the type I TGF-β receptor ALK5 and its downstream substrate Smad2. In addition, Smad2-specific signaling is upregulated in endoglin-induced endothelial cells, whereas it is downregulated upon endoglin gene suppression with small interference RNA (siRNA). The endoglin-dependent upregulation of Smad2 was confirmed using eNOS and pARE promoters, whose activities are known to be Smad2 dependent, as well as with the interference of Smad2 with siRNA, Smurf2, or a dominant negative form of Smad2. Furthermore, increased expression of endoglin in endoglin-inducible endothelial cells or in transfectants resulted in increased levels of Smad2 Protein without affecting the levels of Smad2 mRNA. The increased levels of Smad2 appear to be due to a decreased ubiquitination and proteasome-dependent degradation leading to stabilization of Smad2. These results suggest that endoglin enhances Smad2 Protein levels potentiating TGF-β signaling, and leading to an increased eNOS expression in endothelial cells. J. Cell. Physiol. 210: 456–468, 2007. © 2006 Wiley-Liss, Inc.

  • endoglin increases enos expression by modulating Smad2 Protein levels and Smad2 dependent tgf β signaling
    Journal of Cellular Physiology, 2007
    Co-Authors: Juan F. Santibanez, Jose M Lopeznovoa, Ainhoa Letamendia, Fernando Perezbarriocanal, Marta Saura, Liliana Attisano, Calvin P.h. Vary, Cristoforo Silvestri, Carmelo Bernabeu
    Abstract:

    The endothelial nitric oxide synthase (eNOS) is a critical regulator of cardiovascular homeostasis, whose dysregulation leads to different vascular pathologies. Endoglin is a component of the transforming growth factor beta (TGF-beta) receptor complex present in endothelial cells that is involved in angiogenesis, cardiovascular development, and vascular homeostasis. Haploinsufficient expression of endoglin has been shown to downregulate endothelium-derived nitric oxide in endoglin(+/-) (Eng(+/-)) mice and cultured endothelial cells. Here, we find that TGF-beta1 leads to an increased vasodilatation in Eng(+/+) mice that is severely impaired in Eng(+/-) mice, suggesting the involvement of endoglin in the TGF-beta regulated vascular homeostasis. The endoglin-dependent induction of eNOS occurs at the transcriptional level and is mediated by the type I TGF-beta receptor ALK5 and its downstream substrate Smad2. In addition, Smad2-specific signaling is upregulated in endoglin-induced endothelial cells, whereas it is downregulated upon endoglin gene suppression with small interference RNA (siRNA). The endoglin-dependent upregulation of Smad2 was confirmed using eNOS and pARE promoters, whose activities are known to be Smad2 dependent, as well as with the interference of Smad2 with siRNA, Smurf2, or a dominant negative form of Smad2. Furthermore, increased expression of endoglin in endoglin-inducible endothelial cells or in transfectants resulted in increased levels of Smad2 Protein without affecting the levels of Smad2 mRNA. The increased levels of Smad2 appear to be due to a decreased ubiquitination and proteasome-dependent degradation leading to stabilization of Smad2. These results suggest that endoglin enhances Smad2 Protein levels potentiating TGF-beta signaling, and leading to an increased eNOS expression in endothelial cells.

Juan F. Santibanez - One of the best experts on this subject based on the ideXlab platform.

  • endoglin increases enos expression by modulating Smad2 Protein levels and Smad2 dependent tgf β signaling
    Journal of Cellular Physiology, 2007
    Co-Authors: Jose M Lopeznovoa, Ainhoa Letamendia, Fernando Perezbarriocanal, Marta Saura, Juan F. Santibanez, Liliana Attisano, Calvin P.h. Vary, Cristoforo Silvestri, Carmelo Bernabeu
    Abstract:

    The endothelial nitric oxide synthase (eNOS) is a critical regulator of cardiovascular homeostasis, whose dysregulation leads to different vascular pathologies. Endoglin is a component of the transforming growth factor beta (TGF-β) receptor complex present in endothelial cells that is involved in angiogenesis, cardiovascular development, and vascular homeostasis. Haploinsufficient expression of endoglin has been shown to downregulate endothelium-derived nitric oxide in endoglin+/− (Eng+/−) mice and cultured endothelial cells. Here, we find that TGF-β1 leads to an increased vasodilatation in Eng+/+ mice that is severely impaired in Eng+/− mice, suggesting the involvement of endoglin in the TGF-β regulated vascular homeostasis. The endoglin-dependent induction of eNOS occurs at the transcriptional level and is mediated by the type I TGF-β receptor ALK5 and its downstream substrate Smad2. In addition, Smad2-specific signaling is upregulated in endoglin-induced endothelial cells, whereas it is downregulated upon endoglin gene suppression with small interference RNA (siRNA). The endoglin-dependent upregulation of Smad2 was confirmed using eNOS and pARE promoters, whose activities are known to be Smad2 dependent, as well as with the interference of Smad2 with siRNA, Smurf2, or a dominant negative form of Smad2. Furthermore, increased expression of endoglin in endoglin-inducible endothelial cells or in transfectants resulted in increased levels of Smad2 Protein without affecting the levels of Smad2 mRNA. The increased levels of Smad2 appear to be due to a decreased ubiquitination and proteasome-dependent degradation leading to stabilization of Smad2. These results suggest that endoglin enhances Smad2 Protein levels potentiating TGF-β signaling, and leading to an increased eNOS expression in endothelial cells. J. Cell. Physiol. 210: 456–468, 2007. © 2006 Wiley-Liss, Inc.

  • endoglin increases enos expression by modulating Smad2 Protein levels and Smad2 dependent tgf β signaling
    Journal of Cellular Physiology, 2007
    Co-Authors: Juan F. Santibanez, Jose M Lopeznovoa, Ainhoa Letamendia, Fernando Perezbarriocanal, Marta Saura, Liliana Attisano, Calvin P.h. Vary, Cristoforo Silvestri, Carmelo Bernabeu
    Abstract:

    The endothelial nitric oxide synthase (eNOS) is a critical regulator of cardiovascular homeostasis, whose dysregulation leads to different vascular pathologies. Endoglin is a component of the transforming growth factor beta (TGF-beta) receptor complex present in endothelial cells that is involved in angiogenesis, cardiovascular development, and vascular homeostasis. Haploinsufficient expression of endoglin has been shown to downregulate endothelium-derived nitric oxide in endoglin(+/-) (Eng(+/-)) mice and cultured endothelial cells. Here, we find that TGF-beta1 leads to an increased vasodilatation in Eng(+/+) mice that is severely impaired in Eng(+/-) mice, suggesting the involvement of endoglin in the TGF-beta regulated vascular homeostasis. The endoglin-dependent induction of eNOS occurs at the transcriptional level and is mediated by the type I TGF-beta receptor ALK5 and its downstream substrate Smad2. In addition, Smad2-specific signaling is upregulated in endoglin-induced endothelial cells, whereas it is downregulated upon endoglin gene suppression with small interference RNA (siRNA). The endoglin-dependent upregulation of Smad2 was confirmed using eNOS and pARE promoters, whose activities are known to be Smad2 dependent, as well as with the interference of Smad2 with siRNA, Smurf2, or a dominant negative form of Smad2. Furthermore, increased expression of endoglin in endoglin-inducible endothelial cells or in transfectants resulted in increased levels of Smad2 Protein without affecting the levels of Smad2 mRNA. The increased levels of Smad2 appear to be due to a decreased ubiquitination and proteasome-dependent degradation leading to stabilization of Smad2. These results suggest that endoglin enhances Smad2 Protein levels potentiating TGF-beta signaling, and leading to an increased eNOS expression in endothelial cells.

James N Topper - One of the best experts on this subject based on the ideXlab platform.

  • mekk 1 a component of the stress stress activated Protein kinase c jun n terminal kinase pathway can selectively activate Smad2 mediated transcriptional activation in endothelial cells
    Journal of Biological Chemistry, 1999
    Co-Authors: Jonathan D Brown, Maria R Dichiara, Keith R Anderson, Michael A Gimbrone, James N Topper
    Abstract:

    Abstract Smad Proteins are essential components of the intracellular signaling pathways utilized by members of the transforming growth factor-β (TGF-β) superfamily of growth factors. Certain Smad Proteins (e.g. Smad1, -2, and -3) can act as regulated transcriptional activators, a process that involves phosphorylation of these Proteins by activated TGF-β superfamily receptors. We demonstrate that the intracellular kinase mitogen-activated Protein kinase kinase kinase-1 (MEKK-1), an upstream activator of the stress-activated Protein kinase/c-Jun N-terminal kinase pathway, can participate in Smad2-dependent transcriptional events in cultured endothelial cells. A constitutively active form of MEKK-1 but not mitogen-activated Protein kinase kinase-1 (MEK-1) or TGF-β-activated kinase-1, two distinct intracellular kinases, can specifically activate a Gal4-Smad2 fusion Protein, and this effect correlates with an increase in the phosphorylation state of the Smad2 Protein. These effects do not require the presence of the C-terminal SSXS motif of Smad2 that is the site of TGF-β type 1 receptor-mediated phosphorylation. Activation of Smad2 by active MEKK-1 results in enhanced Smad2-Smad4 interactions, nuclear localization of Smad2 and Smad4, and the stimulation of Smad Protein-transcriptional coactivator interactions in endothelial cells. Overexpression of Smad7 can inhibit the MEKK-1-mediated stimulation of Smad2 transcriptional activity. A physiological level of fluid shear stress, a known activator of endogenous MEKK-1 activity in endothelial cells, can stimulate Smad2-mediated transcriptional activity. These data demonstrate a novel mechanism for activation of Smad Protein-mediated signaling in endothelial cells and suggest that Smad2 may act as an integrator of diverse stimuli in these cells.

  • mekk 1 a component of the stress stress activated Protein kinase c jun n terminal kinase pathway can selectively activate Smad2 mediated transcriptional activation in endothelial cells
    Journal of Biological Chemistry, 1999
    Co-Authors: Jonathan D Brown, Maria R Dichiara, Keith R Anderson, Michael A Gimbrone, James N Topper
    Abstract:

    Smad Proteins are essential components of the intracellular signaling pathways utilized by members of the transforming growth factor-beta (TGF-beta) superfamily of growth factors. Certain Smad Proteins (e.g. Smad1, -2, and -3) can act as regulated transcriptional activators, a process that involves phosphorylation of these Proteins by activated TGF-beta superfamily receptors. We demonstrate that the intracellular kinase mitogen-activated Protein kinase kinase kinase-1 (MEKK-1), an upstream activator of the stress-activated Protein kinase/c-Jun N-terminal kinase pathway, can participate in Smad2-dependent transcriptional events in cultured endothelial cells. A constitutively active form of MEKK-1 but not mitogen-activated Protein kinase kinase-1 (MEK-1) or TGF-beta-activated kinase-1, two distinct intracellular kinases, can specifically activate a Gal4-Smad2 fusion Protein, and this effect correlates with an increase in the phosphorylation state of the Smad2 Protein. These effects do not require the presence of the C-terminal SSXS motif of Smad2 that is the site of TGF-beta type 1 receptor-mediated phosphorylation. Activation of Smad2 by active MEKK-1 results in enhanced Smad2-Smad4 interactions, nuclear localization of Smad2 and Smad4, and the stimulation of Smad Protein-transcriptional coactivator interactions in endothelial cells. Overexpression of Smad7 can inhibit the MEKK-1-mediated stimulation of Smad2 transcriptional activity. A physiological level of fluid shear stress, a known activator of endogenous MEKK-1 activity in endothelial cells, can stimulate Smad2-mediated transcriptional activity. These data demonstrate a novel mechanism for activation of Smad Protein-mediated signaling in endothelial cells and suggest that Smad2 may act as an integrator of diverse stimuli in these cells.

Jonathan D Brown - One of the best experts on this subject based on the ideXlab platform.

  • mekk 1 a component of the stress stress activated Protein kinase c jun n terminal kinase pathway can selectively activate Smad2 mediated transcriptional activation in endothelial cells
    Journal of Biological Chemistry, 1999
    Co-Authors: Jonathan D Brown, Maria R Dichiara, Keith R Anderson, Michael A Gimbrone, James N Topper
    Abstract:

    Abstract Smad Proteins are essential components of the intracellular signaling pathways utilized by members of the transforming growth factor-β (TGF-β) superfamily of growth factors. Certain Smad Proteins (e.g. Smad1, -2, and -3) can act as regulated transcriptional activators, a process that involves phosphorylation of these Proteins by activated TGF-β superfamily receptors. We demonstrate that the intracellular kinase mitogen-activated Protein kinase kinase kinase-1 (MEKK-1), an upstream activator of the stress-activated Protein kinase/c-Jun N-terminal kinase pathway, can participate in Smad2-dependent transcriptional events in cultured endothelial cells. A constitutively active form of MEKK-1 but not mitogen-activated Protein kinase kinase-1 (MEK-1) or TGF-β-activated kinase-1, two distinct intracellular kinases, can specifically activate a Gal4-Smad2 fusion Protein, and this effect correlates with an increase in the phosphorylation state of the Smad2 Protein. These effects do not require the presence of the C-terminal SSXS motif of Smad2 that is the site of TGF-β type 1 receptor-mediated phosphorylation. Activation of Smad2 by active MEKK-1 results in enhanced Smad2-Smad4 interactions, nuclear localization of Smad2 and Smad4, and the stimulation of Smad Protein-transcriptional coactivator interactions in endothelial cells. Overexpression of Smad7 can inhibit the MEKK-1-mediated stimulation of Smad2 transcriptional activity. A physiological level of fluid shear stress, a known activator of endogenous MEKK-1 activity in endothelial cells, can stimulate Smad2-mediated transcriptional activity. These data demonstrate a novel mechanism for activation of Smad Protein-mediated signaling in endothelial cells and suggest that Smad2 may act as an integrator of diverse stimuli in these cells.

  • mekk 1 a component of the stress stress activated Protein kinase c jun n terminal kinase pathway can selectively activate Smad2 mediated transcriptional activation in endothelial cells
    Journal of Biological Chemistry, 1999
    Co-Authors: Jonathan D Brown, Maria R Dichiara, Keith R Anderson, Michael A Gimbrone, James N Topper
    Abstract:

    Smad Proteins are essential components of the intracellular signaling pathways utilized by members of the transforming growth factor-beta (TGF-beta) superfamily of growth factors. Certain Smad Proteins (e.g. Smad1, -2, and -3) can act as regulated transcriptional activators, a process that involves phosphorylation of these Proteins by activated TGF-beta superfamily receptors. We demonstrate that the intracellular kinase mitogen-activated Protein kinase kinase kinase-1 (MEKK-1), an upstream activator of the stress-activated Protein kinase/c-Jun N-terminal kinase pathway, can participate in Smad2-dependent transcriptional events in cultured endothelial cells. A constitutively active form of MEKK-1 but not mitogen-activated Protein kinase kinase-1 (MEK-1) or TGF-beta-activated kinase-1, two distinct intracellular kinases, can specifically activate a Gal4-Smad2 fusion Protein, and this effect correlates with an increase in the phosphorylation state of the Smad2 Protein. These effects do not require the presence of the C-terminal SSXS motif of Smad2 that is the site of TGF-beta type 1 receptor-mediated phosphorylation. Activation of Smad2 by active MEKK-1 results in enhanced Smad2-Smad4 interactions, nuclear localization of Smad2 and Smad4, and the stimulation of Smad Protein-transcriptional coactivator interactions in endothelial cells. Overexpression of Smad7 can inhibit the MEKK-1-mediated stimulation of Smad2 transcriptional activity. A physiological level of fluid shear stress, a known activator of endogenous MEKK-1 activity in endothelial cells, can stimulate Smad2-mediated transcriptional activity. These data demonstrate a novel mechanism for activation of Smad Protein-mediated signaling in endothelial cells and suggest that Smad2 may act as an integrator of diverse stimuli in these cells.

Ainhoa Letamendia - One of the best experts on this subject based on the ideXlab platform.

  • endoglin increases enos expression by modulating Smad2 Protein levels and Smad2 dependent tgf β signaling
    Journal of Cellular Physiology, 2007
    Co-Authors: Jose M Lopeznovoa, Ainhoa Letamendia, Fernando Perezbarriocanal, Marta Saura, Juan F. Santibanez, Liliana Attisano, Calvin P.h. Vary, Cristoforo Silvestri, Carmelo Bernabeu
    Abstract:

    The endothelial nitric oxide synthase (eNOS) is a critical regulator of cardiovascular homeostasis, whose dysregulation leads to different vascular pathologies. Endoglin is a component of the transforming growth factor beta (TGF-β) receptor complex present in endothelial cells that is involved in angiogenesis, cardiovascular development, and vascular homeostasis. Haploinsufficient expression of endoglin has been shown to downregulate endothelium-derived nitric oxide in endoglin+/− (Eng+/−) mice and cultured endothelial cells. Here, we find that TGF-β1 leads to an increased vasodilatation in Eng+/+ mice that is severely impaired in Eng+/− mice, suggesting the involvement of endoglin in the TGF-β regulated vascular homeostasis. The endoglin-dependent induction of eNOS occurs at the transcriptional level and is mediated by the type I TGF-β receptor ALK5 and its downstream substrate Smad2. In addition, Smad2-specific signaling is upregulated in endoglin-induced endothelial cells, whereas it is downregulated upon endoglin gene suppression with small interference RNA (siRNA). The endoglin-dependent upregulation of Smad2 was confirmed using eNOS and pARE promoters, whose activities are known to be Smad2 dependent, as well as with the interference of Smad2 with siRNA, Smurf2, or a dominant negative form of Smad2. Furthermore, increased expression of endoglin in endoglin-inducible endothelial cells or in transfectants resulted in increased levels of Smad2 Protein without affecting the levels of Smad2 mRNA. The increased levels of Smad2 appear to be due to a decreased ubiquitination and proteasome-dependent degradation leading to stabilization of Smad2. These results suggest that endoglin enhances Smad2 Protein levels potentiating TGF-β signaling, and leading to an increased eNOS expression in endothelial cells. J. Cell. Physiol. 210: 456–468, 2007. © 2006 Wiley-Liss, Inc.

  • endoglin increases enos expression by modulating Smad2 Protein levels and Smad2 dependent tgf β signaling
    Journal of Cellular Physiology, 2007
    Co-Authors: Juan F. Santibanez, Jose M Lopeznovoa, Ainhoa Letamendia, Fernando Perezbarriocanal, Marta Saura, Liliana Attisano, Calvin P.h. Vary, Cristoforo Silvestri, Carmelo Bernabeu
    Abstract:

    The endothelial nitric oxide synthase (eNOS) is a critical regulator of cardiovascular homeostasis, whose dysregulation leads to different vascular pathologies. Endoglin is a component of the transforming growth factor beta (TGF-beta) receptor complex present in endothelial cells that is involved in angiogenesis, cardiovascular development, and vascular homeostasis. Haploinsufficient expression of endoglin has been shown to downregulate endothelium-derived nitric oxide in endoglin(+/-) (Eng(+/-)) mice and cultured endothelial cells. Here, we find that TGF-beta1 leads to an increased vasodilatation in Eng(+/+) mice that is severely impaired in Eng(+/-) mice, suggesting the involvement of endoglin in the TGF-beta regulated vascular homeostasis. The endoglin-dependent induction of eNOS occurs at the transcriptional level and is mediated by the type I TGF-beta receptor ALK5 and its downstream substrate Smad2. In addition, Smad2-specific signaling is upregulated in endoglin-induced endothelial cells, whereas it is downregulated upon endoglin gene suppression with small interference RNA (siRNA). The endoglin-dependent upregulation of Smad2 was confirmed using eNOS and pARE promoters, whose activities are known to be Smad2 dependent, as well as with the interference of Smad2 with siRNA, Smurf2, or a dominant negative form of Smad2. Furthermore, increased expression of endoglin in endoglin-inducible endothelial cells or in transfectants resulted in increased levels of Smad2 Protein without affecting the levels of Smad2 mRNA. The increased levels of Smad2 appear to be due to a decreased ubiquitination and proteasome-dependent degradation leading to stabilization of Smad2. These results suggest that endoglin enhances Smad2 Protein levels potentiating TGF-beta signaling, and leading to an increased eNOS expression in endothelial cells.