A novel cellular survival factor--the B2 subunit of vacuolar H+-ATPase inhibits apoptosis.
The ubiquitous vacuolar H(+)-ATPase, a multisubunit proton pump, is essential for intraorganellar acidification. Disruption of its function leads to disturbances of organelle function and cell death. Here, we report that overexpression of the B2 subunit of the H(+)-ATPase inhibits apoptosis. This antiapoptotic effect is not mediated by an increase in H(+)-ATPase activity but through activation of the Ras-mitogen-activated protein kinase (MAPK)-signaling pathway that results in the serine phosphorylation of Bad at residues 112 and 155. Increased Bad phosphorylation reduces its translocation to mitochondria, limits the release of mitochondrial cytochrome c and apoptosis-inducing factor and increases the resistance of the B2 overexpressing cells to apoptosis. Screening experiments of kinase inhibitors, including inhibitors of cAMP-activated protein kinase, protein kinase C, protein kinase B, (MAPK/extracellular signal-regulated (ERK) kinase) MEK and Ste-MEK1(13), a cell permeable ERK activation inhibitor peptide, revealed that the B2 subunit of H(+)-ATPase acts upstream of MEK activation in the MEK/ERK pathway to ameliorate apoptosis.
Li
G
G
Renal Section, Department of Medicine, Boston University Medical Center, Boston University School of Medicine, Boston, MA 02118-2908, USA. gmli@bu.edu
Yang
Q
Q
Krishnan
S
S
Alexander
E A
EA
Borkan
S C
SC
Schwartz
J H
JH
D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D006180:Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; C494819:BAD protein, human; D021122:Protein Subunits; D051025:bcl-Associated Death Protein; D049452:Green Fluorescent Proteins; D045304:Cytochromes c; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D006180:Proton-Translocating ATPases