Ghosh Sourav, Tergaonkar Vinay, Rothlin Carla V, Correa Ricardo G, Bottero Virginie, Bist Pradeep, Verma Inder M, Hunter Tony
Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Cancer Cell. 2006 Sep;10(3):215-26. doi: 10.1016/j.ccr.2006.08.007.
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.
TSC1-TSC2复合物最近被认为与细胞存活反应有关。我们观察到，在DNA损伤或TNFα刺激后，TSC1和TSC2缺陷的小鼠胚胎成纤维细胞（MEFs）中NF-κB信号减弱，同时存活率降低。在TSC2(-/-) MEFs中重建TSC2表达以NF-κB活性依赖的方式挽救了细胞存活。此外，在TSC2(-/-) MEFs中，雷帕霉素介导的对失调的mTOR活性的抑制恢复了NF-κB的激活和细胞存活。这种雷帕霉素介导的效应可通过抑制NF-κB转录激活或抑制ERK1/2 MAP激酶或PI-3K途径而逆转，这些途径位于导致NF-κB激活的信号级联中。这些结果为TSC/Rheb/mTOR途径与NF-κB诱导途径之间的串扰提供了证据，并表明NF-κB作为调节TSC2依赖性细胞存活的重要存活因子发挥作用。
