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TY - JOUR AU - Asnaghi, Laura AU - Calastretti, Angela AU - Bevilacqua, Annamaria AU - D'Agnano, Igea AU - Gatti, Giuliana AU - Canti, Gianfranco AU - Delia, Domenico AU - Capaccioli, Sergio AU - Nicolin, Angelo PY - 2004 DA - 2004/07/01 TI - Bcl-2 phosphorylation and apoptosis activated by damaged microtubules require mTOR and are regulated by Akt JO - Oncogene SP - 5781 EP - 5791 VL - 23 IS - 34 AB - 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. SN - 1476-5594 UR - https://doi.org/10.1038/sj.onc.1207698 DO - 10.1038/sj.onc.1207698 ID - Asnaghi2004 ER -