| First Author | Deleault KM | Year | 2008 |
| Journal | Mol Immunol | Volume | 45 |
| Issue | 1 | Pages | 13-24 |
| PubMed ID | 17606294 | Mgi Jnum | J:124286 |
| Mgi Id | MGI:3721211 | Doi | 10.1016/j.molimm.2007.05.017 |
| Citation | Deleault KM, et al. (2008) Tristetraprolin regulates TNF TNF-alpha mRNA stability via a proteasome dependent mechanism involving the combined action of the ERK and p38 pathways. Mol Immunol 45(1):13-24 |
| abstractText | Tumor necrosis factor-alpha (TNF-alpha) is a central mediator of inflammation. TNF-alpha expression is regulated by transcriptional and post-transcriptional mechanisms, including mRNA stability and translation. Post-transcriptional control operates through cis-elements in the 3' Untranslated-Region of the TNF-alpha mRNA to which trans-acting proteins bind. One of the best characterized trans-acting proteins is Tristetraprolin (TTP), which regulates TNF-alpha message stability. However, the precise mechanisms controlling TNF-alpha message stability are unclear, with data supporting a role for the proteasome, the exosome, and the RNA processing-body (P-body), as well as the involvement of the microRNAs. We examined the effect of proteasome inhibition on endogenous TNF-alpha mRNA stability, TNF-alpha 3'UTR reporter expression and TTP function in the RAW264.7 cells. These data establish that proteasome inhibition stabilized endogenous TNF-alpha mRNA, increased TTP protein levels but inhibited TTP mediated TNF-alpha mRNA decay. Importantly, proteasome inhibition stabilized the TNF-alpha message to the same degree as LPS stimulation. To further characterize the control of TTP function, we examined the combinatorial effect of p38, ERK and JNK activation on TNF-alpha post-transcriptional expression and TTP function. These data establish that TTP mediated TNF-alpha mRNA decay is inhibited by the combined activation of ERK and p38 and not by p38 activation alone. The combined activation of ERK/p38 was sufficient to stabilize endogenous TNF-alpha mRNA to the same degree as LPS stimulation. Together these data indicate that the proteasome is a critical control point for TTP mediated TNF-alpha mRNA decay and activation of both ERK and p38 is required to inhibit TTP function and stabilize TNF-alpha mRNA. |
