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Damaged microtubules can inactivate BCL-2 by means of the mTOR kinase

Oncogene volume 20, pages 6172–6180 (2001)Cite this article

Abstract

Rapamycin, a specific inhibitor of the serine/threonine mTOR kinase, markedly inhibited both cell growth and apoptosis in human B-cell lines. Besides arresting cells in G1 by increasing p27kip1, rapamycin tripled the cellular level of the BCL-2 protein. The activity was dose-dependent and specific for the p27kip1 and BCL-2 proteins. Rapamycin did not affect bcl-2 mRNA although it increased cellular BCL-2 concentration by inhibiting phosphorylation, a mechanism initiating the decay process. To add new insight, we combined rapamycin treatment with treatment by taxol, which, by damaging microtubules, can phosphorylate BCL-2 and activate apoptosis. It was found that the mTOR kinase was activated in cells treated with taxol or with nocodazole although it was inhibited in cells pre-treated with rapamycin. BCL-2 phosphorylation, apoptosis and hyperdiploidy were also inhibited by rapamycin. In contrast, taxol-induced microtubule stabilization or metaphase synchronization were not inhibited by rapamycin. Taken together, these findings indicate that mTOR belongs to the enzymatic cascade that, starting from damaged microtubules, phosphorylates BCL-2. By regulating apoptosis, in addition to the control of a multitude of growth-related pathways, mTOR plays a nodal role in signaling G1 and G2-M events.

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Acknowledgements

We thank Dr JC Lawrence for the Tab1 and Tab2 antibodies, Dr F Navone for the assistance in microtubule staining, Dr P Castagnoli and Dr A Costa for assistance in the flow cytometry and Prof R Silvestrini for assistance in the mitotic index. Finally, we thank Drs D Delia, JC Lawrence and A Quattrone for invaluable suggestions. This work was supported by grants from AIRC, Milan; CNR, Project ACRO; MURST and Istituto Superiore di Sanità, Rome.

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Authors and Affiliations

  1. Department of Pharmacology, University of Milan, Milan, Italy

    Angela Calastretti, Anna Bevilacqua, Cristina Ceriani, Simona Viganò & Angelo Nicolin

  2. Division of Experimental Oncology, Centro di Riferimento Oncologico, Aviano, Italy

    Paola Zancai

  3. Institute of General Pathology, University of Florence, Florence, Italy

    Sergio Capaccioli

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  1. Angela Calastretti
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  2. Anna Bevilacqua
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Correspondence to Angelo Nicolin.

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Calastretti, A., Bevilacqua, A., Ceriani, C. et al. Damaged microtubules can inactivate BCL-2 by means of the mTOR kinase. Oncogene 20, 6172–6180 (2001). https://doi.org/10.1038/sj.onc.1204751

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