IFNγ-induced suppression of β-catenin signaling: evidence for roles of Akt and 14.3.3ζ.
Bottom Line: Akt1 served as a bimodal switch that promotes or inhibits β-catenin transactivation in response to IFNγ stimulation.IFNγ initially promotes β-catenin transactivation through Akt-dependent C-terminal phosphorylation of β-catenin to promote its association with 14.3.3ζ.These results outline a dual function of Akt1 that suppresses IEC proliferation during intestinal inflammation.
Affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322 Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, 07360 Mexico City, Mexico.Show MeSH
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Mentions: Experiments were performed to investigate mechanism(s) by which IFNγ induces expression of Akt1. In colonic epithelial cells, Akt1 expression was reported to be induced by β-catenin transactivation (Dihlmann et al., 2005). Given our findings, we hypothesized that transactivation of β-catenin by Akt after IFNγ exposure at early time points (Figure 1A) was responsible for subsequent increases in Akt1protein expression. As shown in Figure 5A, IFNγ treatment for 2 h increased Akt1 mRNA expression in SW480 cells, and siRNA-mediated down-regulation of β-catenin inhibited this effect. We also investigated the possibility that β-catenin transactivation by Akt and 14.3.3ζ may regulate Akt1 expression after IFNγ treatment. Indeed, as shown in Figure 5B, IFNγ treatment resulted in an increase in Akt1 mRNA that was prevented by pharmacologic inhibition of Akt kinase activity. Furthermore, forced expression of 14.3.3ζ increased Akt1 mRNA levels that were further increased when the cells were treated with IFNγ (Figure 5B). Of importance, pharmacologic inhibition of Akt activity abrogated the increase in Akt1 mRNA mediated by 14.3.3ζ overexpression in the absence or presence of IFNγ (Figure 5B). Finally, we investigated the effect of 14.3.3ζ on the regulation of Dkk-1, a Wnt inhibitor known to be induced by IFNγ during inflammation (Nava et al., 2010). As shown in Supplemental Figure S10, up-regulation of DKK-1 mRNA levels was observed in IECs transiently expressing 14.3.3ζ. Thus, taken together, these results suggested that activation of β-catenin by Akt is necessary to induce expression of Akt1 and Dkk-1 to establish a feedback loop that inhibits Wnt/β-catenin and IEC proliferation.
Affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322 Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, 07360 Mexico City, Mexico.