Regulation of endoplasmic reticulum Ca2+ dynamics by proapoptotic BCL-2 family members.
Uncontrolled cytosolic Ca(2+) overload is a common cause of cell death in several pathological conditions. Recent evidences reveal a more regulated role for intracellular Ca(2+) stores in controlling cell death. Proteins of the BCL-2 family include anti- and proapoptotic members that control the mitochondrial amplification loop of apoptosis. The antiapoptotic protein BCL-2 prevents this mitochondrial loop, while the "multidomain" proapoptotic proteins BAX and BAK are crucial to initiate it. BCL-2, BAX and BAK localize also to the endoplasmic reticulum (ER), the main intracellular Ca(2+) store. Overexpression of BCL-2 reduces resting ER Ca(2+) and death in response to apoptotic stimuli that mobilize Ca(2+). Our recent data indicate that multidomain proapoptotics also influence Ca(2+) metabolism. Cells deficient for Bax, Bak (DKO) display lowered steady state ER Ca(2+) concentrations ([Ca(2+)](er)) and secondarily decreased mitochondrial Ca(2+) uptake. Genetic and pharmacologic correction of [Ca(2+)](er) indicates that it controls death in response to Ca(2+)-dependent, mitochondria utilizing signals such as oxidative stress and lipid mediators; and that it participates in the regulation of the apoptotic response to most intrinsic stimuli, such as staurosporine. Thus, BAX and BAK control apoptosis not only at the mitochondria, but also at the ER, an obligate checkpoint for Ca(2+)-dependent apoptotic stimuli.
Oakes
Scott A
SA
Howard Hughes Medical Institute, Dana Farber Cancer Institute, Boston, USA.
Opferman
Joseph T
JT
Pozzan
Tullio
T
Korsmeyer
Stanley J
SJ
Scorrano
Luca
L
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
C494772:BAK1 protein, human; C494826:BAX protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D002118:Calcium