Bcl-2 phosphorylation and apoptosis activated by damaged microtubules require mTOR and are regulated by Akt

Laura Asnaghi, Angela Calastretti, Annamaria Bevilacqua, Igea D'Agnano, Giuliana Gatti, Gianfranco Canti, Domenico Delia, Sergio Capaccioli, Angelo Nicolin

Research output: Contribution to journalArticlepeer-review

104 Scopus citations


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 p70S6K Thr421/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.

Original languageEnglish (US)
Pages (from-to)5781-5791
Number of pages11
Issue number34
StatePublished - Jul 29 2004


  • Akt
  • Apoptosis
  • BCL-2
  • Microtubules
  • mTOR
  • p70S6K

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research


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