| First Author | Ladner KJ | Year | 2003 |
| Journal | J Biol Chem | Volume | 278 |
| Issue | 4 | Pages | 2294-303 |
| PubMed ID | 12431991 | Mgi Jnum | J:81730 |
| Mgi Id | MGI:2449882 | Doi | 10.1074/jbc.M207129200 |
| Citation | Ladner KJ, et al. (2003) Tumor necrosis factor-regulated biphasic activation of NF-kappa B is required for cytokine-induced loss of skeletal muscle gene products. J Biol Chem 278(4):2294-303 |
| abstractText | NF-kappaB activation is classically defined as a transient response initiated by the degradation of IkappaB inhibitor proteins leading to nuclear import of NF-kappaB and culminating with the resynthesis of IkappaBalpha and subsequent inactivation of the transcription factor. Although this type of regulation is considered the paradigm for NF-kappaB activation, other regulatory profiles are known to exist. By far the most common of these is chronic or persistent activation of NF-kappaB. In comparison, regulation of NF-kappaB in a biphasic manner represents a profile that is scarcely documented and whose biological significance remains poorly understood. Here we show using differentiated skeletal muscle cells, that tumor necrosis factor (TNF) induces NF-kappaB activation in a biphasic manner. Unlike the first transient phase, which is terminated within 1 h of cytokine addition, the second phase persists for an additional 24-36 h. Biphasic activation is mediated at both the levels of NF-kappaB DNA binding and transactivation function, and both phases are dependent on the IKK/26 S proteasome pathway. We find that regulation of the first transient phase is mediated by the degradation and subsequent resynthesis of IkappaBalpha, as well as by a TNF-induced expression of A20. Second phase activity correlates with persistent down-regulation of both IkappaBalpha and IkappaBbeta proteins, derived from a continuous TNF signal. Finally, we demonstrate that inhibition of NF-kappaB prior to initiation of the second phase of activity inhibits cytokine-mediated loss of muscle proteins. We propose that the biphasic activation of NF-kappaB in response to TNF may play a key regulatory role in skeletal muscle wasting associated with cachexia. |
