Endothelin-1 induces glut1 transcription through enhanced interaction between Sp1 and NF-kappaB transcription factors.
We have shown previously that endothelin-1 (ET-1) induction of Glut1 transcription is mediated by ET-1 responsive elements on enhancer 2, via both protein kinase Cepsilon (PKCepsilon)- and p42/p44 mitogen-activated protein kinase (MAPK)-dependent pathways. In the present study, we further explored the molecular mechanism involved. By using mutation constructs of luciferase reporter driven by Glut1 promoter/enhancers, chromatin immunoprecipitation and co-immunoprecipitation experiments, we were able to demonstrate that cooperative interaction between NF-kappaB and Sp1 were required to enhance Glut1 transcription in response to ET-1. While ET-1 may induce Sp1 expression via both PKC-and MAPK-dependent pathways, activation of NF-kappaB by ET-1 is mediated by a PKCepsilon/reactive oxygen species (ROS) cascade. Taken together, these results suggest that by activating NF-kappaB via PKCepsilon/ROS cascade and increasing Sp1 expression through both PKCepsilon- and MAPK-dependent pathways, ET-1 may activate Glut1 transcription by enhancing interaction between nuclear NF-kappaB and Sp1 as well as their binding to enhancer 2.
Kao
Ying-Shiun
YS
Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, Republic of China.
Fong
Jim C
JC
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism*; D017930:Genes, Reporter; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D019332:Endothelin-1; D051272:Glucose Transporter Type 1; D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C495678:Slc2a1 protein, mouse; D016329:Sp1 Transcription Factor; D051996:Transcription Factor RelA; D008156:Luciferases; D051744:Protein Kinase C-epsilon; D020928:Mitogen-Activated Protein Kinases