Asnaghi, Laura; Calastretti, Angela; Bevilacqua, Annamaria; D'Agnano, Igea; Gatti, Giuliana; Canti, Gianfranco; Delia, Domenico; Capaccioli, Sergio; Nicolin, Angelo
The serine/threonine kinase mTOR, the major sensor of cell growth along the PI3K/Akt pathway, can be activated by agents acting on microtubules. Damaged microtubules induce phosphorylation of the Bcl-2 protein and lower the threshold of programmed cell death, both of which are inhibited by rapamycin. In HEK293 cells expressing Akt mutants, the level of Bcl-2 phosphorylation and the threshold of apoptosis induced by taxol or by nocodazole are significantly modified. In cells expressing dominant-negative Akt (DN-Akt), Bcl-2 phosphorylation and p70S6KThr421/Ser424 phosphorylation induced by taxol or nocodazole were significantly enhanced as compared to cells expressing constitutively active Akt (CA-Akt) and inhibited by rapamycin. Moreover, DN-Akt cells were more sensitive to antitubule agents than CA-Akt cells. In nocodazole-treated HEK293 cells sorted according to cell cycle, the p70S6KThr421/Ser424 phosphorylation was associated to the G2/M fraction. More relevant, nocodazole inhibited, in a dose-response manner, mTOR phosphorylation at Ser2448. This activity, potentiated in DN-Akt cells, was not detectable in CA-Akt cells. Our results suggest that death signals originating from damaged microtubules in G2/M can compete with G1 survival pathways at the level of mTOR. These findings have implications for cancer therapy and drug resistance.
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Text Mining Data
mTOR → Akt: " Bcl-2 phosphorylation and apoptosis activated by damaged microtubules require mTOR
and are regulated
mTOR → Bcl-2: " Bcl-2 phosphorylation and apoptosis activated by damaged microtubules require mTOR and are regulated by Akt "
Akt — Bcl-2: " Bcl-2 phosphorylation and apoptosis activated by damaged microtubules require mTOR and are regulated by Akt "
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