Regulation of NF-κB Activation through a Novel PI-3K-Independent and PKA-Akt-Dependent Pathway in Human Umbilical Vein Endothelial CellsReport as inadecuate




Regulation of NF-κB Activation through a Novel PI-3K-Independent and PKA-Akt-Dependent Pathway in Human Umbilical Vein Endothelial Cells - Download this document for free, or read online. Document in PDF available to download.

The transcription factor NF-κB regulates numerous inflammatory diseases, and proteins involved in the NF-κB-activating signaling pathway are important therapeutic targets. In human umbilical vein endothelial cells HUVECs, TNF-α-induced IκBα degradation and p65-RelA phosphorylation regulate NF-κB activation. These are mediated by IKKs IκB kinases viz. IKKα, β and γ which receive activating signals from upstream kinases such as Akt. Akt is known to be positively regulated by PI-3K phosphoinositide-3-kinase and differentially regulated via Protein kinase A PKA in various cell types. However, the involvement of PKA-Akt cross talk in regulating NF-κB in HUVECs has not been explored yet. Here, we examined the involvement of PKA-Akt cross-talk in HUVECs using a novel compound, 2-methyl-pyran-4-one-3-O-β-D-2′,3′,4′,6′-tetra-O-acetyl glucopyranoside MPTAG. We observed that MPTAG does not directly inhibit IKK-β but prevents TNF-α-induced activation of IKK-β by blocking its association with Akt and thereby inhibits NF-κB activation. Interestingly, our results also revealed that inhibitory effect of MPTAG on Akt and NF-κB activation was unaffected by wortmannin, and was completely abolished by H-89 treatment in these cells. Thus, MPTAG-mediated inhibition of TNF-α-induced Akt activation was independent of PI-3K and dependent on PKA. Most importantly, MPTAG restores the otherwise repressed activity of PKA and inhibits the TNF-α-induced Akt phosphorylation at both Thr308 and Ser473 residues. Thus, we demonstrate for the first time the involvement of PKA-Akt cross talk in NF-κB activation in HUVECs. Also, MPTAG could be useful as a lead molecule for developing potent therapeutic molecules for diseases where NF-κB activation plays a key role.



Author: Sakshi Balwani, Rituparna Chaudhuri, Debkumar Nandi, Parasuraman Jaisankar, Anurag Agrawal, Balaram Ghosh

Source: http://plos.srce.hr/



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