Akt kinase reducing endoplasmic reticulum Ca2+ release protects cells from Ca2+-dependent apoptotic stimuli.
The proto-oncogene Akt is a potent inhibitor of apoptosis, and it is activated in many human cancers. A number of recent studies have highlighted the importance of the inositol 1,4,5-trisphosphate (IP3) receptor(IP3R) in mediating calcium (Ca2+) transfer from the endoplasmic reticulum (ER) to the mitochondriain several models of apoptosis. Akt is a serine-threonine kinase and recent data indicate the IP3R as a target of its phosphorylation activity. Here we show that HeLa cells, overexpressing the constitutively active myristoylated/palmitylatedAKT1 (m/p-AKT1), were found to have a reduced Ca2+ release from ER after stimulation with agonist coupled to the generation of IP3. In turn, this affected cytosolic and mitochondria Ca2+ response after Ca2+release from the ER induced either by agonist stimulation or by apoptotic stimuli releasing Ca2+ from intracellular stores. Most importantly, this alteration of ER Ca2+ content and release, reduces significantly cellular sensitivity to Ca2+ mediated proapoptotic stimulation. These results reveal a primary role of Akt in shaping intracellular Ca2+ homeostasis, that may underlie its protective role against some proapoptotic stimuli.
Marchi
Saverio
S
Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation (ICSI), University of Ferrara, Via Borsari 46, I-44100 Ferrara, Italy.
Rimessi
Alessandro
A
Giorgi
Carlotta
C
Baldini
Claudio
C
Ferroni
Letizia
L
Rizzuto
Rosario
R
Pinton
Paolo
P
D017209:Apoptosis; D016718:Arachidonic Acid / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*
D053496:Inositol 1,4,5-Trisphosphate Receptors; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016718:Arachidonic Acid; D006861:Hydrogen Peroxide; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium