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Robert Ballotti - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of the Phosphatidylinositol 3-Kinase/p70S6-Kinase Pathway Induces B16 Melanoma Cell Differentiation
Journal of Biological Chemistry, 1996Co-Authors: Roser Busca, Jean-paul Ortonne, Corine Bertolotto, Robert BallottiAbstract:Abstract α-Melanocyte-stimulating hormone and cAMP-Elevating Agents are known to induce B16 cell differentiation, characterized by increased melanin synthesis and dendrite outgrowth. In order to elucidate intracellular signaling pathways involved in this differentiation process, we focused our interest on the phosphatidylinositol 3-kinase/p70S6-kinase pathway. The specific inhibition of phosphatidylinositol 3-kinase by LY294002 markedly stimulated dendrite outgrowth, thus mimicking the action of cAMP-Elevating Agents on B16 cell morphology. In addition, LY294002 and rapamycin, a specific p70S6-kinase inhibitor, were found to independently stimulate tyrosinase expression, thus increasing melanin synthesis. In an attempt to better dissect the molecular mechanisms triggered by cAMP to induce melanoma cell differentiation, we examined the effects of a cAMP-Elevating Agent forskolin, on both phosphatidylinositol 3-kinase and p70S6-kinase activities. Specific kinase assays revealed that forskolin partially inhibited phosphatidylinositol 3-kinase activity and completely blocked p70S6-kinase activity and phosphorylation. In conclusion, our results clearly demonstrate that the inhibition of phosphatidylinositol 3-kinase and p70S6-kinase is involved in the regulation of B16 cell differentiation. Furthermore, we provide evidence which suggests that cAMP-induced melanogenesis and dendricity are, at least partially, mediated by the cAMP inhibition of the phosphatidylinositol 3-kinase/p70S6-kinase signaling pathway.
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inhibition of the phosphatidylinositol 3 kinase p70s6 kinase pathway induces b16 melanoma cell differentiation
Journal of Biological Chemistry, 1996Co-Authors: Roser Busca, Jean-paul Ortonne, Corine Bertolotto, Robert BallottiAbstract:Abstract α-Melanocyte-stimulating hormone and cAMP-Elevating Agents are known to induce B16 cell differentiation, characterized by increased melanin synthesis and dendrite outgrowth. In order to elucidate intracellular signaling pathways involved in this differentiation process, we focused our interest on the phosphatidylinositol 3-kinase/p70S6-kinase pathway. The specific inhibition of phosphatidylinositol 3-kinase by LY294002 markedly stimulated dendrite outgrowth, thus mimicking the action of cAMP-Elevating Agents on B16 cell morphology. In addition, LY294002 and rapamycin, a specific p70S6-kinase inhibitor, were found to independently stimulate tyrosinase expression, thus increasing melanin synthesis. In an attempt to better dissect the molecular mechanisms triggered by cAMP to induce melanoma cell differentiation, we examined the effects of a cAMP-Elevating Agent forskolin, on both phosphatidylinositol 3-kinase and p70S6-kinase activities. Specific kinase assays revealed that forskolin partially inhibited phosphatidylinositol 3-kinase activity and completely blocked p70S6-kinase activity and phosphorylation. In conclusion, our results clearly demonstrate that the inhibition of phosphatidylinositol 3-kinase and p70S6-kinase is involved in the regulation of B16 cell differentiation. Furthermore, we provide evidence which suggests that cAMP-induced melanogenesis and dendricity are, at least partially, mediated by the cAMP inhibition of the phosphatidylinositol 3-kinase/p70S6-kinase signaling pathway.
Roser Busca - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of the Phosphatidylinositol 3-Kinase/p70S6-Kinase Pathway Induces B16 Melanoma Cell Differentiation
Journal of Biological Chemistry, 1996Co-Authors: Roser Busca, Jean-paul Ortonne, Corine Bertolotto, Robert BallottiAbstract:Abstract α-Melanocyte-stimulating hormone and cAMP-Elevating Agents are known to induce B16 cell differentiation, characterized by increased melanin synthesis and dendrite outgrowth. In order to elucidate intracellular signaling pathways involved in this differentiation process, we focused our interest on the phosphatidylinositol 3-kinase/p70S6-kinase pathway. The specific inhibition of phosphatidylinositol 3-kinase by LY294002 markedly stimulated dendrite outgrowth, thus mimicking the action of cAMP-Elevating Agents on B16 cell morphology. In addition, LY294002 and rapamycin, a specific p70S6-kinase inhibitor, were found to independently stimulate tyrosinase expression, thus increasing melanin synthesis. In an attempt to better dissect the molecular mechanisms triggered by cAMP to induce melanoma cell differentiation, we examined the effects of a cAMP-Elevating Agent forskolin, on both phosphatidylinositol 3-kinase and p70S6-kinase activities. Specific kinase assays revealed that forskolin partially inhibited phosphatidylinositol 3-kinase activity and completely blocked p70S6-kinase activity and phosphorylation. In conclusion, our results clearly demonstrate that the inhibition of phosphatidylinositol 3-kinase and p70S6-kinase is involved in the regulation of B16 cell differentiation. Furthermore, we provide evidence which suggests that cAMP-induced melanogenesis and dendricity are, at least partially, mediated by the cAMP inhibition of the phosphatidylinositol 3-kinase/p70S6-kinase signaling pathway.
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inhibition of the phosphatidylinositol 3 kinase p70s6 kinase pathway induces b16 melanoma cell differentiation
Journal of Biological Chemistry, 1996Co-Authors: Roser Busca, Jean-paul Ortonne, Corine Bertolotto, Robert BallottiAbstract:Abstract α-Melanocyte-stimulating hormone and cAMP-Elevating Agents are known to induce B16 cell differentiation, characterized by increased melanin synthesis and dendrite outgrowth. In order to elucidate intracellular signaling pathways involved in this differentiation process, we focused our interest on the phosphatidylinositol 3-kinase/p70S6-kinase pathway. The specific inhibition of phosphatidylinositol 3-kinase by LY294002 markedly stimulated dendrite outgrowth, thus mimicking the action of cAMP-Elevating Agents on B16 cell morphology. In addition, LY294002 and rapamycin, a specific p70S6-kinase inhibitor, were found to independently stimulate tyrosinase expression, thus increasing melanin synthesis. In an attempt to better dissect the molecular mechanisms triggered by cAMP to induce melanoma cell differentiation, we examined the effects of a cAMP-Elevating Agent forskolin, on both phosphatidylinositol 3-kinase and p70S6-kinase activities. Specific kinase assays revealed that forskolin partially inhibited phosphatidylinositol 3-kinase activity and completely blocked p70S6-kinase activity and phosphorylation. In conclusion, our results clearly demonstrate that the inhibition of phosphatidylinositol 3-kinase and p70S6-kinase is involved in the regulation of B16 cell differentiation. Furthermore, we provide evidence which suggests that cAMP-induced melanogenesis and dendricity are, at least partially, mediated by the cAMP inhibition of the phosphatidylinositol 3-kinase/p70S6-kinase signaling pathway.
José Augusto Nogueira-machado - One of the best experts on this subject based on the ideXlab platform.
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cAMP activates the generation of reactive oxygen species and inhibits the secretion of IL-6 in peripheral blood mononuclear cells from type 2 diabetic patients.
Oxidative medicine and cellular longevity, 2009Co-Authors: Camila Armond Isoni, Erica Abreu Borges, Clara Araújo Veloso, Rafael Teixeira Mattos, Míriam Martins Chaves, José Augusto Nogueira-machadoAbstract:Peripheral blood mononuclear cells (PBMNC) from patients with type 2 diabetes (DM2) have generated higher levels of reactive oxygen species (ROS) that were higher than those in cells from healthy individuals. In the presence of a cAMP-Elevating Agent, ROS production was significantly activated in PBMNC from DM2 patients but it was inhibited in cells from healthy subjects. Higher levels of IL-6 has been detected in the supernatant of PBMNC cultures from DM2 patients in comparison with healthy controls. When cells were cultured in the presence of a cAMP-Elevating Agent, the level of IL-6 decreased has by 46% in the supernatant of PBMNC from DM2 patients but it remained unaltered in controls. No correlations between ROS and IL-6 levels in PBMNC from DM2 patients or controls have been observed. Secretions of IL-4 or IFN by PBMNC from patients or controls have not been affected by the elevation of cAMP. cAMP elevating Agents have activated the production of harmful reactive oxidant down modulated IL-6 secretion by these cells from DM2 patients, suggesting an alteration in the metabolic response possibly due to hyperglicemia. The results suggest that cAMP may play an important role in the pathogenesis of diabetes.
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Modulation of the production of Reactive Oxygen Species (ROS) by cAMP-Elevating Agents in granulocytes from diabetic patients: an Akt/PKB- dependent phenomenon
Diabetes & metabolism, 2006Co-Authors: José Augusto Nogueira-machado, F.c Lima E Silva, Ep Cunha, Calsolari, Daniela Caldeira Costa, C.s. Perilo, Bc Horta, Ic Ferreira, Míriam Martins ChavesAbstract:Summary Background Granulocytes from healthy subjects and from patients suffering from diabetes mellitus present differences in reactivity to stimulation with cyclic nucleotide-elevating Agents. The production of reactive oxygen species (ROS) is inhibited in cells from non-diabetic subjects following such stimulation, but activated through a PKA-independent signaling pathway in granulocytes from type 1 and type 2 diabetic patients. The aim of the present study was to understand better the changes in signaling mechanisms induced by the disease. Methods ROS production in granulocytes from healthy subjects and from type 1 and type 2 diabetic patients was measured using a luminol-dependent chemiluminescence assay. Granulocytes were stimulated by the addition of the cAMP-Elevating Agent dibutyryl cAMP. In some experiments, granulocytes were pre-treated with an inhibitor of PKA or Akt/PKB prior to cAMP stimulation. Results Intracellular elevation of cAMP induced a PKA-dependent and Akt/PKB-independent inhibition of ROS production in granulocytes from healthy subjects, but a significant activation in cells from both type 1 and type 2 diabetic patients. Most significantly, activation of ROS generation in cells from diabetic patients was shown to be Akt/PKB-dependent and PKA-independent. Conclusions These results suggest that chronic hyperglycaemia could induce metabolic adaptation in cAMP-related signaling mechanisms. Epac (exchange protein directly activated by cAMP) is a novel cAMP receptor besides PKA involved in different signaling pathways. The cAMP-stimulated inverse ROS response in granulocytes from type 1 and type 2 diabetic patients may be due to a change in signaling pathways from cAMP/PKA to cAMP/Epac/Akt/PKB. These preliminary results require further studies in order to evaluate their consequences on innate immunity and pathogenesis of diabetes mellitus.
Míriam Martins Chaves - One of the best experts on this subject based on the ideXlab platform.
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cAMP activates the generation of reactive oxygen species and inhibits the secretion of IL-6 in peripheral blood mononuclear cells from type 2 diabetic patients.
Oxidative medicine and cellular longevity, 2009Co-Authors: Camila Armond Isoni, Erica Abreu Borges, Clara Araújo Veloso, Rafael Teixeira Mattos, Míriam Martins Chaves, José Augusto Nogueira-machadoAbstract:Peripheral blood mononuclear cells (PBMNC) from patients with type 2 diabetes (DM2) have generated higher levels of reactive oxygen species (ROS) that were higher than those in cells from healthy individuals. In the presence of a cAMP-Elevating Agent, ROS production was significantly activated in PBMNC from DM2 patients but it was inhibited in cells from healthy subjects. Higher levels of IL-6 has been detected in the supernatant of PBMNC cultures from DM2 patients in comparison with healthy controls. When cells were cultured in the presence of a cAMP-Elevating Agent, the level of IL-6 decreased has by 46% in the supernatant of PBMNC from DM2 patients but it remained unaltered in controls. No correlations between ROS and IL-6 levels in PBMNC from DM2 patients or controls have been observed. Secretions of IL-4 or IFN by PBMNC from patients or controls have not been affected by the elevation of cAMP. cAMP elevating Agents have activated the production of harmful reactive oxidant down modulated IL-6 secretion by these cells from DM2 patients, suggesting an alteration in the metabolic response possibly due to hyperglicemia. The results suggest that cAMP may play an important role in the pathogenesis of diabetes.
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Modulation of the production of Reactive Oxygen Species (ROS) by cAMP-Elevating Agents in granulocytes from diabetic patients: an Akt/PKB- dependent phenomenon
Diabetes & metabolism, 2006Co-Authors: José Augusto Nogueira-machado, F.c Lima E Silva, Ep Cunha, Calsolari, Daniela Caldeira Costa, C.s. Perilo, Bc Horta, Ic Ferreira, Míriam Martins ChavesAbstract:Summary Background Granulocytes from healthy subjects and from patients suffering from diabetes mellitus present differences in reactivity to stimulation with cyclic nucleotide-elevating Agents. The production of reactive oxygen species (ROS) is inhibited in cells from non-diabetic subjects following such stimulation, but activated through a PKA-independent signaling pathway in granulocytes from type 1 and type 2 diabetic patients. The aim of the present study was to understand better the changes in signaling mechanisms induced by the disease. Methods ROS production in granulocytes from healthy subjects and from type 1 and type 2 diabetic patients was measured using a luminol-dependent chemiluminescence assay. Granulocytes were stimulated by the addition of the cAMP-Elevating Agent dibutyryl cAMP. In some experiments, granulocytes were pre-treated with an inhibitor of PKA or Akt/PKB prior to cAMP stimulation. Results Intracellular elevation of cAMP induced a PKA-dependent and Akt/PKB-independent inhibition of ROS production in granulocytes from healthy subjects, but a significant activation in cells from both type 1 and type 2 diabetic patients. Most significantly, activation of ROS generation in cells from diabetic patients was shown to be Akt/PKB-dependent and PKA-independent. Conclusions These results suggest that chronic hyperglycaemia could induce metabolic adaptation in cAMP-related signaling mechanisms. Epac (exchange protein directly activated by cAMP) is a novel cAMP receptor besides PKA involved in different signaling pathways. The cAMP-stimulated inverse ROS response in granulocytes from type 1 and type 2 diabetic patients may be due to a change in signaling pathways from cAMP/PKA to cAMP/Epac/Akt/PKB. These preliminary results require further studies in order to evaluate their consequences on innate immunity and pathogenesis of diabetes mellitus.
Kazushige Yokota - One of the best experts on this subject based on the ideXlab platform.
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Stimulation of fat storage by prostacyclin and selective agonists of prostanoid IP receptor during the maturation phase of cultured adipocytes.
Cytotechnology, 2016Co-Authors: Ferdous Khan, Kohji Nishimura, Mitsuo Jisaka, Pinky Karim Syeda, Michael Nii N. Nartey, Mohammad Shahidur Rahman, Mohammad Safiqul Islam, Fumiaki Shono, Kazushige YokotaAbstract:We have previously shown that cultured adipocytes have the ability to biosynthesize prostaglandin (PG) I2 called alternatively as prostacyclin during the maturation phase by the positive regulation of gene expression of PGI synthase and the prostanoid IP receptor. To clarify how prostacyclin regulates adipogenesis, we investigated the effects of prostacyclin and the specific agonists or antagonists for the IP receptor on the storage of fats during the maturation phase of cultured adipocytes. Exogenous PGI2 and the related selective agonists for the IP receptor including MRE-269 and treprostinil rescued the storage of fats attenuated by aspirin, a cyclooxygenase inhibitor. On the other hand, selective antagonists for IP such as CAY10441 and CAY10449 were effective to suppress the accumulation of fats as GW9662, a specific antagonist for peroxisome proliferator-activated receptor (PPAR)γ. Thus, pro-adipogenic action of prostacyclin can be explained by the action mediated through the IP receptor expressed at the maturation stage of adipocytes. Cultured adipocytes incubated with each of PGI2 and MRE-269 together with troglitazone, an activator for PPARγ, exhibited additively higher stimulation of fats storage than with either compound alone. The combined effect of MRE-269 and troglitazone was almost abolished by co-incubation with GW9662, but not with CAY10441. Increasing concentrations of troglitazone were found to reverse the inhibitory effect of CAY10441 in a dose-dependent manner while those of MRE-269 failed to rescue adipogenesis suppressed by GW9662, indicating the critical role of the PPARγ activation as a downstream factor for the stimulated adipogenesis through the IP receptor. Treatment of cultured adipocytes with cell permeable stable cAMP analogues or forskolin as a cAMP elevating Agent partly restored the inhibitory effect of aspirin. However, excess levels of cAMP stimulated by forskolin attenuated adipogenesis. Supplementation with H-89, a cell permeable inhibitor for protein kinase A (PKA), had no effect on the promoting action of PGI2 or MRE-269 along with aspirin on the storage of fats, suggesting that the promotion of adipogenesis mediated by the IP receptor does not require the PKA activity.
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Pretreatment of cultured preadipocytes with arachidonic acid during the differentiation phase without a cAMP-Elevating Agent enhances fat storage after the maturation phase.
Prostaglandins & other lipid mediators, 2016Co-Authors: Ferdous Khan, Kohji Nishimura, Mitsuo Jisaka, Pinky Karim Syeda, Michael Nii N. Nartey, Mohammad Shahidur Rahman, Mohammad Safiqul Islam, Fumiaki Shono, Kazushige YokotaAbstract:Arachidonic acid (AA) and the related prostanoids exert complex effects on the adipocyte differentiation depending on the culture conditions and life stages. Here, we investigated the effect of the pretreatment of cultured 3T3-L1 preadipocytes with exogenous AA during the differentiation phase without 3-isobutyl-1-methylxanthine (IBMX), a cAMP-Elevating Agent, on the storage of fats after the maturation phase. This pretreatment with AA stimulated appreciably adipogenesis after the maturation phase as evident with the up-regulated gene expression of adipogenic markers. The stimulatory effect of the pretreatment with AA was attenuated by the co-incubation with each of cyclooxygenase (COX) inhibitors. Among exogenous prostanoids and related compounds, the pretreatment with MRE-269, a selective agonist of the IP receptor for prostaglandin (PG) I2, strikingly stimulated the storage of fats in adipocytes. The gene expression analysis of arachidonate COX pathway revealed that the transcript levels of inducible COX-2, membrane-bound PGE synthase-1, and PGF synthase declined more greatly in cultured preadipocytes treated with AA. By contrast, the expression levels of COX-1, cytosolic PGE synthase, and PGI synthase remained constitutive. The treatment of cultured preadipocytes with AA resulted in the decreased synthesis of PGE2 and PGF2α serving as anti-adipogenic PGs although the biosynthesis of pro-adipogenic PGI2 was up-regulated during the differentiation phase. Moreover, the gene expression levels of EP4 and FP, the respective prostanoid receptors for PGE2 and PGF2α, were gradually suppressed by the supplementation with AA, whereas that of IP for PGI2 remained relatively constant. Collectively, these results suggest the predominant role of endogenous PGI2 in the stimulatory effect of the pretreatment of cultured preadipoccytes with AA during the differentiation phase without IBMX on adipogenesis after the maturation phase.