Extracellular Signal-regulated Kinase Regulation of Tumor Necrosis Factor-α mRNA Nucleocytoplasmic Transport Requires TAP-NxT1 Binding and the AU-rich Element
Journal of Biological Chemistry
Tumor necrosis factor-␣ (TNF-␣) production is regulated by transcriptional and posttranscriptional mechanisms. Lipopolysaccharide activates the NFB pathway increasing TNF-␣ transcription. Lipopolysaccharide also activates the mitogenactivated protein kinase pathways, resulting in stabilization and enhanced translation of the TNF-␣ message. In addition, nuclear export of the TNF-␣ mRNA is a posttranscriptionally regulated process involving the Tpl2-ERK pathway and requiring the presence of the
... F-␣ AU-rich element (ARE). We demonstrate that nuclear export of the TNF-␣ message requires not only the TNF-␣ 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-␣ mRNA nuclear export operates specifically through ERK1. Finally, we examined the role of two established TNF-␣ 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-␣ 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.