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Original Article

Rakesh K. Srivastava^a, Carl Y. Sasaki^a, J. Marie Hardwick^b, and Dan L. Longo^a

^a From the Laboratory of Immunology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224-6825
^b Department of Molecular Biology and Immunology, Johns Hopkins School of Public Health, Baltimore, Maryland 21205
Laboratory of Immunology, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr., Box 9, Baltimore, MD 21224-6825.410-558-8284410-558-8480

rakeshs{at}vax.grc.nia.nih.gov

Bcl-2 inhibits apoptosis induced by a variety of stimuli, including chemotherapy drugs and glucocorticoids. It is generally accepted that Bcl-2 exerts its antiapoptotic effects mainly by dimerizing with proapoptotic members of the Bcl-2 family such as Bax and Bad. However, the mechanism of the antiapoptotic effects is unclear. Paclitaxel and other drugs that disturb microtubule dynamics kill cells in a Fas/Fas ligand (FasL)-dependent manner; antibody to FasL inhibits paclitaxel-induced apoptosis. We have found that Bcl-2 overexpression leads to the prevention of chemotherapy (paclitaxel)-induced expression of FasL and blocks paclitaxel-induced apoptosis. The mechanism of this effect is that Bcl-2 prevents the nuclear translocation of NFAT (nuclear factor of activated T lymphocytes, a transcription factor activated by microtubule damage) by binding and sequestering calcineurin, a calcium-dependent phosphatase that must dephosphorylate NFAT to move to the nucleus. Without NFAT nuclear translocation, the FasL gene is not transcribed. Thus, it appears that paclitaxel and other drugs that disturb microtubule function kill cells at least in part through the induction of FasL. Furthermore, Bcl-2 antagonizes drug-induced apoptosis by inhibiting calcineurin activation, blocking NFAT nuclear translocation, and preventing FasL expression. The effects of Bcl-2 can be overcome, at least partially, through phosphorylation of Bcl-2. Phosphorylated Bcl-2 cannot bind calcineurin, and NFAT activation, FasL expression, and apoptosis can occur after Bcl-2 phosphorylation.

Key Words: Fas ligand • apoptosis • NFAT • Bcl-2 • paclitaxel

R.K. Srivastava is a recipient of the National Research Council Fellowship.

© 1999 The Rockefeller University Press

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