Essential role of tuberous sclerosis genes TSC1 and TSC2 in NF-κB activation and cell survival

Summary C1-TSC2 complex has recently been implicated in cell survival responses. We observed that NF-κB signaling is attenuated in TSC1- and TSC2-deficient MEFs concomitant with reduced survival following DNA damage or TNFα stimulation. Reconstitution of TSC2 expression in TSC2−/− MEFs rescued survival in an NF-κB activity-dependent manner. Furthermore, in TSC2−/− MEFs, the rapamycin-mediated inhibition of deregulated mTOR activity restored NF-κB activation and survival. This rapamycin-mediated effect was reversed by inhibition of NF-κB transcriptional activation or by inhibition of ERK1/2 MAP kinase or PI-3K pathways, which lie on signaling cascades that lead to NF-κB activation. These results provide evidence for a crosstalk between the TSC/Rheb/mTOR pathway and the NF-κB induction pathways and indicate that NF-κB functions as an important survival factor that regulates TSC2-dependent cell survival.