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

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