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

  • Ghosh S
  • Tergaonkar V
  • Rothlin C
 et al. 
  • 44

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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.

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Authors

  • Sourav Ghosh

  • Vinay Tergaonkar

  • Carla Rothlin

  • Ricardo Correa

  • Virginie Bottero

  • Pradeep Bist

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