[NF-kappaB regulates GADD45beta expression during acute inflammation]
>>J Biol Chem. 2005 Mar 29; [Epub ahead of print]
NF-kappaB and not the MAP kinase signaling pathway regulates GADD45beta expression during acute inflammation.
Zhang N, Ahsan MH, Zhu L, Sambucetti LC, Purchio AF, West DB.
Xenogen Corp, Alameda, CA 94501.
The GADD45 (growth arrest and DNA damage-inducible) family of genes is involved in the regulation of cell cycle progression and apoptosis. To study signaling pathways affecting GADD45beta expression and to examine systematically in vivo the GADD45beta expression in tissues following various toxic stresses, we created a transgenic mouse by fusing the GADD45beta promoter to firefly luciferase (Gadd45beta-luc). In vivo GADD45beta expression was assessed by measuring the luciferase activity in the Gadd45beta-luc transgenic mouse. We found that a number of agents that induce oxidative stress, such as sodium arsenite, CCl4, lipopolysaccharide (LPS) or TNF-alpha, are able to induce luciferase expression throughout the entire animal. In liver, spleen, lung, intestine, kidney and heart, we observed an induction of luciferase activity after LPS treatment, which correlates with an increase of GADD45beta mRNA in these tissues. Processes that induce DNA damage activate the NF-kappaB signaling pathway. Several inhibitors of the NF-kappaB signaling pathway, including dexamethasone, thalidomide and a proteasome inhibitor, bortezomib, showed inhibitory effects on LPS-induced GADD45beta expression as indicated by a decrease of the luciferase activity. Northern blot analysis confirmed a broad inhibitory effect of bortezomib on LPS induced GADD45beta mRNA expression in spleen, lung and intestine. MAP kinase inhibitors had transient and inconsistent effects on LPS-induced luciferase expression. Our data are consistent with the notion that NF-kappaB, but not the MAP kinase signaling pathways, is involved in the in vivo regulation of GADD45beta expression.<<
Interesting that all of the compounds tested were NF-KappaB inhibitors, but apparently the proteasome inhibitor had the broadest effect on the expression of these genes. Also, another example of why Xenogen matters.
Anyhow, GADD45beta seems to be active in prostate, liver, and breast cancer, perhaps others. Seems to work with NF-KappaB to protect cancer cells from radiation, so this supports work showing Bortezomib is an IR sensitizer.
Cheers, Tuck |
