Wnt-1 dependent activation of the survival factor NF-kappa B in PC12 cells

Expression of the Wnt-1 oncogene in PC12 cells induces morphological and bi ochemical changes, including upregulation of cell adhesion and lack of diff erentiation in response to growth factors. The survival of PC12 cells is kn own to be mediated in part by phosphatidylinositol-3 kinase (PI-3 kinase)-d ependent activation of the transcription factor nuclear factor-kappa B (NF- kappa B). We investigated the effect of Wnt-1 expression on cell survival a nd NF-kappa B activation using PC12 cells expressing Wnt-1 (PG12/Wnt1) and a reporter vector in which firefly luciferase expression is under the contr ol of NF-kappa B consensus sequences. Serum deprivation caused apoptosis an d decreased NF-kappa B activity in wild type PC12 cells. PC12/Wnt-1 cells s howed less apoptosis in the absence of serum, and the levels of NF-kappa B activity were higher than in wild type PC12 cells. NF-kappa B activity was also increased by the transient expression of Wnt-1 in PC12 cells and it wa s completely inhibited in both PC12 and PC12/Wnt-1 cells by a dominant nega tive mutant I kappa B-alpha that has been shown to prevent NF-kappa B activ ation. Agents known to inhibit NF-kappa B-induced apoptosis in PC12 as well as in PC12/Wnt-1 cells, indicating a role of NF-kappa B activation in the anti-apoptotic effect of Wnt-1. Inhibition of PI-3 kinase with wortmannin, or with a dominant negative p85 regulatory subunit of the PI-3 kinase, bloc ked NF-kappa B activity in PC12 cells but caused only partial inhibition in PC12/Wnt-1 cells. The effect of Wnt-1 in activating NF-kappa B can be mimi cked by inhibition of glycogen synthase kinase-3 beta (GSK-3 beta) with lit hium or with a dominant negative GSK3 beta. Our results show that expressio n of Wnt-1 increases survival of PC12 cells in the absence of serum by acti vating the anti-apoptotic factor NF-kappa B. Wnt-1-induced activation of NF -kappa B is partially independent of PI-3 kinase and can be mimicked by inh ibition of GSK-3 beta. J. Neurosci. Res. 61.21-32, 2000. (C) 2000 Wiley-Lis s, Inc.