Publication Date:
1999-04-09
Description:
The Ca2+-activated protein phosphatase calcineurin induces apoptosis, but the mechanism is unknown. Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. The Ca2+-induced dephosphorylation of BAD correlated with its dissociation from 14-3-3 in the cytosol and translocation to mitochondria where Bcl-xL resides. In hippocampal neurons, L-glutamate, an inducer of Ca2+ influx and calcineurin activation, triggered mitochondrial targeting of BAD and apoptosis, which were both suppressible by coexpression of a dominant-inhibitory mutant of calcineurin or pharmacological inhibitors of this phosphatase. Thus, a Ca2+-inducible mechanism for apoptosis induction operates by regulating BAD phosphorylation and localization in cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, H G -- Pathan, N -- Ethell, I M -- Krajewski, S -- Yamaguchi, Y -- Shibasaki, F -- McKeon, F -- Bobo, T -- Franke, T F -- Reed, J C -- AG-1593/AG/NIA NIH HHS/ -- CA-69381/CA/NCI NIH HHS/ -- HD25938/HD/NICHD NIH HHS/ -- etc. -- New York, N.Y. -- Science. 1999 Apr 9;284(5412):339-43.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10195903" target="_blank"〉PubMed〈/a〉
Keywords:
14-3-3 Proteins
;
Animals
;
*Apoptosis
;
Calcineurin/genetics/*metabolism
;
Calcineurin Inhibitors
;
Calcium/*metabolism/pharmacology
;
Carrier Proteins/chemistry/*metabolism
;
Cell Line
;
Cells, Cultured
;
Dimerization
;
Enzyme Inhibitors/pharmacology
;
Glutamic Acid/pharmacology
;
Hippocampus/cytology
;
Humans
;
Mitochondria/metabolism
;
Neurons/cytology/metabolism
;
Phosphorylation
;
Protein-Serine-Threonine Kinases/metabolism
;
Proteins/metabolism
;
Proto-Oncogene Proteins c-bcl-2/metabolism
;
Rats
;
Recombinant Fusion Proteins/metabolism
;
Transfection
;
*Tyrosine 3-Monooxygenase
;
bcl-Associated Death Protein
;
bcl-X Protein
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
