Publication Date:
2003-03-08
Description:
BAX and BAK are "multidomain" proapoptotic proteins that initiate mitochondrial dysfunction but also localize to the endoplasmic reticulum (ER). Mouse embryonic fibroblasts deficient for BAX and BAK (DKO cells) were found to have a reduced resting concentration of calcium in the ER ([Ca2+]er) that results in decreased uptake of Ca2+ by mitochondria after Ca2+ release from the ER. Expression of SERCA (sarcoplasmic-endoplasmic reticulum Ca2+ adenosine triphosphatase) corrected [Ca2+]er and mitochondrial Ca2+ uptake in DKO cells, restoring apoptotic death in response to agents that release Ca2+ from intracellular stores (such as arachidonic acid, C2-ceramide, and oxidative stress). In contrast, targeting of BAX to mitochondria selectively restored apoptosis to "BH3-only" signals. A third set of stimuli, including many intrinsic signals, required both ER-released Ca2+ and the presence of mitochondrial BAX or BAK to fully restore apoptosis. Thus, BAX and BAK operate in both the ER and mitochondria as an essential gateway for selected apoptotic signals.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scorrano, Luca -- Oakes, Scott A -- Opferman, Joseph T -- Cheng, Emily H -- Sorcinelli, Mia D -- Pozzan, Tullio -- Korsmeyer, Stanley J -- R37CA50239/CA/NCI NIH HHS/ -- T32HL07627/HL/NHLBI NIH HHS/ -- TCP02016/Telethon/Italy -- New York, N.Y. -- Science. 2003 Apr 4;300(5616):135-9. Epub 2003 Mar 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Department of Pathology and Medicine, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12624178" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
*Apoptosis
;
Arachidonic Acid/pharmacology
;
Calcium/*metabolism
;
Calcium Signaling
;
Calcium-Transporting ATPases/metabolism
;
Cell Fractionation
;
Cell Line, Transformed
;
Cells, Cultured
;
Endoplasmic Reticulum/*metabolism
;
Histamine/pharmacology
;
Hydrogen Peroxide/pharmacology
;
Ionomycin/pharmacology
;
Membrane Proteins/*metabolism
;
Mice
;
Mice, Knockout
;
Microscopy, Confocal
;
Microscopy, Immunoelectron
;
Mitochondria/metabolism
;
Proto-Oncogene Proteins/*metabolism
;
*Proto-Oncogene Proteins c-bcl-2
;
Recombinant Fusion Proteins/metabolism
;
Sarcoplasmic Reticulum Calcium-Transporting ATPases
;
Sphingosine/*analogs & derivatives/pharmacology
;
bcl-2 Homologous Antagonist-Killer Protein
;
bcl-2-Associated X Protein
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink