Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and Bcl-2

  title={Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and Bcl-2},
  author={Futoshi Shibasaki and Eisaku Kondo and Tadaatsu Akagi and Frank McKeon},
It is not known how the protein Bcl-2 inhibits cell death induced by calcium signalling and growth-factor withdrawal1–3. Here we report that Bcl-2 forms a tight complex with calcineurin, resulting in the targeting of calcineurin to Bcl-2 sites on cytoplasmic membranes, and show that this interaction is dependent on the BH4 domain of Bcl-2. Calcineurin bound to Bcl-2 is an active phosphatase but is unable to promote the nuclear translocation of NF-AT, a transcription-factor required for… 
Linkage of the BH4 Domain of Bcl-2 and the Nuclear Factor κB Signaling Pathway for Suppression of Apoptosis*
Adenovirus-mediated delivery of an IκBα mutant to prevent NFκB activation impaired the ability of Bcl-2 to suppress apoptosis provoked by TNFα plus cycloheximide in ventricular myocytes.
Bcl-2–Mediated Drug Resistance
It appears that paclitaxel and other drugs that disturb microtubule function kill cells at least in part through the induction of FasL, and Bcl-2 antagonizes drug-induced apoptosis by inhibiting calcineurin activation, blocking NFAT nuclear translocation, and preventing FasL expression.
Reversible Phosphorylation of Bcl2 following Interleukin 3 or Bryostatin 1 Is Mediated by Direct Interaction with Protein Phosphatase 2A*
It is shown that phosphorylation of Bcl2 occurs rapidly after the addition of agonist to IL-3-deprived cells and can be reversed by the action of an okadaic acid (OA)-sensitive phosphatase.
Targeting Bcl-2 based on the interaction of its BH4 domain with the inositol 1,4,5-trisphosphate receptor.
Inhibition of Transcription Factor Activity by Nuclear Compartment-associated Bcl-2*
The results suggest that nuclear compartment-associated Bcl-2 suppresses transcriptional activity of multiple transcription factors and does not interfere with NFκB activation but prevents entrance of its active subunits to the nucleus.
Bcl-2 and Bcl-XL serve an anti-inflammatory function in endothelial cells through inhibition of NF-κB
Bcl-2 and Bcl-XL belong to a cytoprotective response that counteracts proapoptotic and proinflammatory insults and restores the physiological anti-inflammatory phenotype to the EC.
Bcl-2 Localized at the Nuclear Compartment Induces Apoptosis after Transient Overexpression*
Bcl-2 has a dual role as both a protector and a killer and that the ability to switch roles depends on B cl-2 subcellular localization, and the results demonstrate a novel, pro-apoptotic function for nuclear BCl-2.
Btf, a Novel Death-Promoting Transcriptional Repressor That Interacts with Bcl-2-Related Proteins
The chromosomal localization ofbtf (6q22-23) maps to a region that is deleted in some cancers, consistent with a role for Btf in tumor suppression, and may represent a novel tumor suppressor gene residing in a unique pathway by which the Bcl-2 family can regulate apoptosis.
Posttranslational Modification of Bcl-2 Facilitates Its Proteasome-Dependent Degradation: Molecular Characterization of the Involved Signaling Pathway
A direct protective role is demonstrated for Bcl-2 phosphorylation by MAP kinase against apoptotic challenges to endothelial cells and other cells and it is shown that oxidative stress mediates TNF-α-stimulated proteolytic degradation of B cl-2 by reducingMAP kinase activity.


Role of kinases and the phosphatase calcineurin in the nuclear shuttling of transcription factor NF-AT4
Calcium signalling induces an association between NF-AT4 and calcineurin, and that these molecules are transported, as a complex, to the nucleus, where calcineURin continues to dephosphorylate NF- AT4.
Role of membrane anchor domain of Bcl-2 in suppression of apoptosis caused by E1B-defective adenovirus.
When the predicted transmembrane domain of the Bcl-2 signal anchor was replaced with that of the signal anchor of the yeast outer mitochondrial membrane protein, Mas70p, the B cl-2/Mas70p hybrid was found to be very similar to Bcl -2 in its distribution within transfected KB cells, in its ability to heterodimerize with Bax, and in its able to suppress apoptosis.
Cross talk between cell death and cell cycle progression: BCL-2 regulates NFAT-mediated activation.
Select genetic aberrations in the apoptotic pathway reveal a cell autonomous coregulation of activation, as well as a cysteine protease inhibitor that also blocks apoptosis.
Calcineurin functions in Ca(2+)-activated cell death in mammalian cells
It is demonstrated that a calcium-independent calcineurin mutant induces apoptosis in the absence of calcium, and that this apoptotic response is a direct consequence of calcineURin's phosphatase activity.
Interactions among members of the Bcl-2 protein family analyzed with a yeast two-hybrid system.
  • T. Sato, M. Hanada, H. G. Wang
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1994
The findings suggest a model whereby Bax and Bcl-X-S differentially regulate B cl-2 function, and indicate that requirements for BCl-2/Bax heterodimerization may be different from those for Bcl/Bcl-2 homodimerized.
Multiple Bcl-2 family members demonstrate selective dimerizations with Bax.
The susceptibility to apoptosis is determined by multiple competing dimerizations in which Bax may be a common partner, and a Gly-159-->Ala substitution in BH1 of Bcl-xL disrupted its heterodimerization with Bax and abrogated its inhibition of apoptosis in mammalian cells.
X-ray and NMR structure of human Bcl-xL, an inhibitor of programmed cell death
The arrangement of the α-helices in Bcl-xL is reminiscent of the membrane translocation domain of bacterial toxins, in particular diphia toxin and the colicins, and may provide a clue to the mechanism of action of the B cl-2 family of proteins.