Bcl-2–Mediated Drug Resistance
Open Access
- 19 July 1999
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 190 (2), 253-266
- https://doi.org/10.1084/jem.190.2.253
Abstract
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.Keywords
This publication has 83 references indexed in Scilit:
- Screening of a library of phage-displayed peptides identifies human Bcl-2 as a taxol-binding protein 1 1Edited by I. A. WilsonJournal of Molecular Biology, 1999
- Transcriptional Regulation of the Human FasL Promoter-Enhancer RegionPublished by Elsevier ,1998
- Role of kinases and the phosphatase calcineurin in the nuclear shuttling of transcription factor NF-AT4Nature, 1996
- A role for CD95 ligand in preventing graft rejectionNature, 1995
- Fas-mediated cytotoxicity by freshly isolated natural killer cells.The Journal of Experimental Medicine, 1995
- Fas(CD95)/FasL interactions required for programmed cell death after T-cell activationNature, 1995
- Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomasNature, 1995
- NF-ATp: a transcription factor required for the co-ordinate induction of several cytokine genesImmunology Today, 1994
- Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosisNature, 1992
- The mechanism of action of cyclosporin A and FK506Immunology Today, 1992