Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Cell Survival / drug effects
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DNA Damage
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Fibroblasts
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MAP Kinase Signaling System
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Mice
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Mice, Knockout
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Monomeric GTP-Binding Proteins / metabolism
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NF-kappa B / metabolism*
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Neuropeptides / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering / genetics
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Ras Homolog Enriched in Brain Protein
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Transcription, Genetic / genetics
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Necrosis Factor-alpha / pharmacology
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
Substances
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NF-kappa B
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Neuropeptides
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RHEB protein, human
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RNA, Small Interfering
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Ras Homolog Enriched in Brain Protein
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TSC1 protein, human
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TSC2 protein, human
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Tsc1 protein, mouse
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Tsc2 protein, mouse
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Tuberous Sclerosis Complex 1 Protein
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Tuberous Sclerosis Complex 2 Protein
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Tumor Necrosis Factor-alpha
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Tumor Suppressor Proteins
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Monomeric GTP-Binding Proteins