Several cell stresses induce nuclear factor-kappaB (NF-κB) activation, which include irradiation, oxidation, and UV. Interestingly, serum-starving stress-induced NF-κB activation in COS cells, but not in COS-A717 cells. COSA717 is a mutant cell line of COS cells that is defective of the NF-κB signaling pathway. We isolated genes with compensating activity for the NF-κB pathway and one gene encoded the G protein b2 (Gb2). Gb2 is one of the G rotein-coupled receptor signaling effectors. In COS-A717 cells, Gb2 expression is significantly reduced. In Gb2 cDNA-transfected COS-A717 cells, the NF-κB activity was increased along with the recovery of Gb2 expression. Furthermore, serum-starving stress induced the NF-κB activity in Gb2-transfected COS-A717 cells. Consistently, the serum-starved COS cells with siRNA-reduced Gb2 protein expression showed decreased NF-κB activity. These results indicate that Gb2 is required for starvation-induced NF-κB activation and constitutive NF-kB activity. We propose that serum contains some molecule(s) that strongly inhibits NF-κB activation mediated through Gβ2 signaling. DNA and Cell Biology, 31(11), pp.1636-1644; 2012