Essential role of tuberous sclerosis genes TSC1 and TSC2 in NF-kappaB activation and cell survival.
The TSC1-TSC2 complex has recently been implicated in cell survival responses. We observed that NF-kappaB signaling is attenuated in TSC1- and TSC2-deficient MEFs concomitant with reduced survival following DNA damage or TNFalpha stimulation. Reconstitution of TSC2 expression in TSC2(-/-) MEFs rescued survival in an NF-kappaB activity-dependent manner. Furthermore, in TSC2(-/-) MEFs, the rapamycin-mediated inhibition of deregulated mTOR activity restored NF-kappaB activation and survival. This rapamycin-mediated effect was reversed by inhibition of NF-kappaB transcriptional activation or by inhibition of ERK1/2 MAP kinase or PI-3K pathways, which lie on signaling cascades that lead to NF-kappaB activation. These results provide evidence for a crosstalk between the TSC/Rheb/mTOR pathway and the NF-kappaB induction pathways and indicate that NF-kappaB functions as an important survival factor that regulates TSC2-dependent cell survival.
Ghosh
Sourav
S
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Tergaonkar
Vinay
V
Rothlin
Carla V
CV
Correa
Ricardo G
RG
Bottero
Virginie
V
Bist
Pradeep
P
Verma
Inder M
IM
Hunter
Tony
T
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D005347:Fibroblasts; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D000076205:Ras Homolog Enriched in Brain Protein; D014158:Transcription, Genetic / Q000235:genetics; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D016328:NF-kappa B; D009479:Neuropeptides; C490211:RHEB protein, human; D034741:RNA, Small Interfering; D000076205:Ras Homolog Enriched in Brain Protein; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020559:Monomeric GTP-Binding Proteins