Extracellular signal-regulated kinase regulation of tumor necrosis factor-alpha mRNA nucleocytoplasmic transport requires TAP-NxT1 binding and the AU-rich element.
Tumor necrosis factor-alpha (TNF-alpha) production is regulated by transcriptional and posttranscriptional mechanisms. Lipopolysaccharide activates the NFkappaB pathway increasing TNF-alpha transcription. Lipopolysaccharide also activates the mitogen-activated protein kinase pathways, resulting in stabilization and enhanced translation of the TNF-alpha message. In addition, nuclear export of the TNF-alpha mRNA is a posttranscriptionally regulated process involving the Tpl2-ERK pathway and requiring the presence of the TNF-alpha AU-rich element (ARE). We demonstrate that nuclear export of the TNF-alpha message requires not only the TNF-alpha ARE but also the interaction of the proteins TAP and NxT1, both of which are involved in nucleocytoplasmic transport of mRNA. Through the use of dominant negative ERK1 and ERK2, we establish that control of TNF-alpha mRNA nuclear export operates specifically through ERK1. Finally, we examined the role of two established TNF-alpha ARE-binding proteins, HuR and tristetraprolin, that shuttle between the nucleus and cytoplasm. These data demonstrate that neither tristetraprolin nor HuR is required for TNF-alpha mRNA export. It is unclear at this time if ARE-binding protein(s) directly interact with the TAP-NxT1 complex, if each complex is independently targeted by ERK1, or if only one complex is targeted.
Skinner
Stephen J
SJ
Veterans Affairs Medical Center, White River Junction, Vermont 05009.
Deleault
Kristen M
KM
Department of Medicine, Dartmouth Medical School, Dartmouth College, Lebanon, New Hampshire 03756.
Fecteau
Ryan
R
Department of Medicine, Dartmouth Medical School, Dartmouth College, Lebanon, New Hampshire 03756.
Brooks
Seth A
SA
Veterans Affairs Medical Center, White River Junction, Vermont 05009; Department of Medicine, Dartmouth Medical School, Dartmouth College, Lebanon, New Hampshire 03756; Department of Microbiology and Immunology, Dartmouth College, Lebanon, New Hampshire 03756. Electronic address: seth.brooks@dartmouth.edu.
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D021581:Active Transport, Cell Nucleus; D000818:Animals; D000954:Antigens, Surface / Q000737:chemistry; D001483:Base Sequence; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D048049:Extracellular Signal-Regulated MAP Kinases; D005786:Gene Expression Regulation; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry; D051816:Tristetraprolin / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D016328:NF-kappa B; D029543:Nucleocytoplasmic Transport Proteins; C402484:Nxt1 protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C486171:Tap1 protein, mouse; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases