Wnt‐1 dependent activation of the survival factor NF‐κB in PC12 cells (original) (raw)

Expression of the Wnt-1 oncogene in PC12 cells induces morphological and biochemical changes, including upregulation of cell adhesion and lack of differentiation in response to growth factors. The survival of PC12 cells is known to be mediated in part by phosphatidylinositol-3 kinase (PI-3 kinase)-dependent activation of the transcription factor nuclear factor-B (NF-B). We investigated the effect of Wnt-1 expression on cell survival and NF-B activation using PC12 cells expressing Wnt-1 (PC12/Wnt1) and a reporter vector in which firefly luciferase expression is under the control of NF-B consensus sequences. Serum deprivation caused apoptosis and decreased NF-B activity in wild type PC12 cells. PC12/Wnt-1 cells showed less apoptosis in the absence of serum, and the levels of NF-B activity were higher than in wild type PC12 cells. NF-B activity was also increased by the transient expression of Wnt-1 in PC12 cells and it was completely inhibited in both PC12 and PC12/Wnt-1 cells by a dominant negative mutant IB-␣ that has been shown to prevent NF-B activation. Agents known to inhibit NF-B-induced apoptosis in PC12 as well as in PC12/Wnt-1 cells, indicating a role of NF-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, blocked NF-B activity in PC12 cells but caused only partial inhibition in PC12/Wnt-1 cells. The effect of Wnt-1 in activating NF-B can be mimicked by inhibition of glycogen synthase kinase-3␤ (GSK-3␤) with lithium or with a dominant negative GSK-3␤. Our results show that expression of Wnt-1 increases survival of PC12 cells in the absence of serum by activating the anti-apoptotic factor NF-B. Wnt-1-induced activation of NF-B is partially independent of PI-3 kinase and can be mimicked by inhibition of GSK-3␤. J. Neurosci.