Sphingosine 1-phosphate （S1P）, a pleiotropic lysophospholipid, regulates signal transduction pathway via Gprotein-coupled receptors termed S1P1-5 in several types of the cells including lymphocytes. Higher levels of...Sphingosine 1-phosphate （S1P）, a pleiotropic lysophospholipid, regulates signal transduction pathway via Gprotein-coupled receptors termed S1P1-5 in several types of the cells including lymphocytes. Higher levels of S1P4 mRNA as well as S1P1 mRNA are expressed in lymphoid tissues such as the spleen, thymus, lymph nodes, and Payer＇s patches. In contrast to S1P1 that plays an essential role in lymphocyte egress, little is known about the role of S1P4 in immune system. In this study, we found that S1P at 10 to 100 nM significantly induced the cell migration and the significant levels of S1P1 and S1P4 mRNA were expressed in mouse CD4 T cells, D10.G4.1 mouse Th2 cells, and EL-4.IL-2 mouse thymoma cells. In D10.G4.1 and EL-4.IL-2 cells, S1P-induced migration was almost completely inhibited by pretreatment with pertussis toxin, Clostoridium difficile toxin B, and （S）-enantiomer of FTY720-phosphate, a potent agonist at S1P1 and S1P4. The members of the Rho family small GTPase, Cdc42 and Rac were activated by S1P stimulation in these cells. The transfection with dominant negative or constitutively active forms of Cdc42 and Rac revealed that the activation of both Cdc42 and Rac is essential for S1P-induced migration of these cells. The immunoprecipitation assays using CHO cells co-expressing both S1P4 and S1P1 receptors indicated that S1P4 and S1P1 are associated on the cell surface. These results suggest that the association of S1P4 and S1PI plays an important role in migratory response of mouse T cells toward S1P.展开更多
Histone deacetylase 1(HDAC1)is an important epigenetic controller involvedin transcriptional regulation throughmodification of chromatin structure.Genetic and epigenetic changes and deregulation of signal transduction...Histone deacetylase 1(HDAC1)is an important epigenetic controller involvedin transcriptional regulation throughmodification of chromatin structure.Genetic and epigenetic changes and deregulation of signal transduction pathways have been implicated in the development of breast cancer.Downregulation of estrogen receptor a(ERa)expression is one of the mechanisms behind the acquisition of endocrine resistance.Sustained and increased hormone and growth factor receptor signaling in breast cancer cells contribute to resistance to endocrine therapy.Both HDACs and the PI3K/mTOR signaling pathway are becoming promising targets in breast cancer,reversing also acquired hormone resistance.Here we show how mitogens,activating the PI3K/mTOR pathway,trigger the phosphorylation of HDAC1 in breast cancer cells,which is completely dependent on the activity of the p70 S6 kinase(S6K1).Our findings show that S6K1,overexpressed in many breast cancers,controls HDAC1-dependent transcriptional regulation of ERa levels upon mitogenic stimuli,controlling HDAC1 recruitment to the ERa promoter.Furthermore,cell treatment with both mTOR and HDACs inhibitors shows an additive effect in inhibiting breast cancer proliferation.This confirms the novel cross-talk between the HDAC1 and PI3K pathways with clinical implications towards the treatment of this malignant disease.展开更多
文摘Sphingosine 1-phosphate （S1P）, a pleiotropic lysophospholipid, regulates signal transduction pathway via Gprotein-coupled receptors termed S1P1-5 in several types of the cells including lymphocytes. Higher levels of S1P4 mRNA as well as S1P1 mRNA are expressed in lymphoid tissues such as the spleen, thymus, lymph nodes, and Payer＇s patches. In contrast to S1P1 that plays an essential role in lymphocyte egress, little is known about the role of S1P4 in immune system. In this study, we found that S1P at 10 to 100 nM significantly induced the cell migration and the significant levels of S1P1 and S1P4 mRNA were expressed in mouse CD4 T cells, D10.G4.1 mouse Th2 cells, and EL-4.IL-2 mouse thymoma cells. In D10.G4.1 and EL-4.IL-2 cells, S1P-induced migration was almost completely inhibited by pretreatment with pertussis toxin, Clostoridium difficile toxin B, and （S）-enantiomer of FTY720-phosphate, a potent agonist at S1P1 and S1P4. The members of the Rho family small GTPase, Cdc42 and Rac were activated by S1P stimulation in these cells. The transfection with dominant negative or constitutively active forms of Cdc42 and Rac revealed that the activation of both Cdc42 and Rac is essential for S1P-induced migration of these cells. The immunoprecipitation assays using CHO cells co-expressing both S1P4 and S1P1 receptors indicated that S1P4 and S1P1 are associated on the cell surface. These results suggest that the association of S1P4 and S1PI plays an important role in migratory response of mouse T cells toward S1P.
基金This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro to S.C.(AIRC IG5732,AIRC IG12075)S.Ci.was supported by a fellowship from Fondazione Umberto Veronesi(FUV).
文摘Histone deacetylase 1(HDAC1)is an important epigenetic controller involvedin transcriptional regulation throughmodification of chromatin structure.Genetic and epigenetic changes and deregulation of signal transduction pathways have been implicated in the development of breast cancer.Downregulation of estrogen receptor a(ERa)expression is one of the mechanisms behind the acquisition of endocrine resistance.Sustained and increased hormone and growth factor receptor signaling in breast cancer cells contribute to resistance to endocrine therapy.Both HDACs and the PI3K/mTOR signaling pathway are becoming promising targets in breast cancer,reversing also acquired hormone resistance.Here we show how mitogens,activating the PI3K/mTOR pathway,trigger the phosphorylation of HDAC1 in breast cancer cells,which is completely dependent on the activity of the p70 S6 kinase(S6K1).Our findings show that S6K1,overexpressed in many breast cancers,controls HDAC1-dependent transcriptional regulation of ERa levels upon mitogenic stimuli,controlling HDAC1 recruitment to the ERa promoter.Furthermore,cell treatment with both mTOR and HDACs inhibitors shows an additive effect in inhibiting breast cancer proliferation.This confirms the novel cross-talk between the HDAC1 and PI3K pathways with clinical implications towards the treatment of this malignant disease.
