| First Author | Zhang G | Year | 2013 |
| Journal | FASEB J | Volume | 27 |
| Issue | 7 | Pages | 2893-901 |
| PubMed ID | 23568773 | Mgi Jnum | J:199941 |
| Mgi Id | MGI:5506662 | Doi | 10.1096/fj.12-222711 |
| Citation | Zhang G, et al. (2013) Signaling mechanism of tumor cell-induced up-regulation of E3 ubiquitin ligase UBR2. FASEB J 27(7):2893-901 |
| abstractText | The N-end rule pathway contributes significantly to accelerated muscle proteolysis mediated by the ubiquitin-proteasome pathway in various catabolic conditions. UBR2 (aka E3alpha-II) is the only known E3 ubiquitin ligase of the N-end rule pathway that is up-regulated by cachectic stimuli including proinflammatory cytokines and tumors. However, the signaling mechanism through which UBR2 is up-regulated remains undetermined. Here we identify a signaling pathway that mediates tumor cell-induced up-regulation of UBR2. UBR2 expression in C2C12 myotubes was up-regulated by conditioned medium from Lewis lung carcinoma cells or C26 colon adenocarcinoma cells, which was blocked by a pharmacological inhibitor of p38alpha/beta mitogen-activated protein kinase (MAPK), SB202190. Similarly, SB202190 administration (i.p.) abolished UBR2 up-regulation in the tibialis anterior of LLC tumor-bearing mice. Genetic gain and loss of function assays in C2C12 myotubes indicated that tumor-induced activation of the p38beta isoform is sufficient and necessary for UBR2 up-regulation. In addition, UBR2 up-regulation required p38beta-mediated phosphorylation of CCAAT/enhancer binding protein (C/EBP)-beta Thr-188, which was critical to C/EBPbeta binding to the UBR2 promoter. Furthermore, luciferase reporter assay revealed that the C/EBPbeta binding motif in the UBR2 promoter is a functional C/EBPbeta-responsive cis-element that enhances the promoter activity on activation by p38beta. Finally, genetic ablation of C/EBPbeta blocked UBR2 up-regulation in LLC tumor-bearing mice. These results suggest that UBR2 up-regulation in cachectic muscle is mediated by the p38beta-C/EBPbeta signaling pathway responsible for the bulk of tumor-induced muscle proteolysis. |
