Intracellular acidification induces apoptosis by stimulating ICE-like protease activity.
ICE-like protease activation and DNA fragmentation are preceded by a decrease in intracellular pH (pHi) during apoptosis in the IL-3 dependent cell line BAF3. Acidification occurs after 7 hours in cells deprived of IL-3 and after 4 hours when cells are treated with etoposide, close to the time of detection of ICE-like protease activity. Increasing extracellular pH reduces ICE-like protease activation and DNA fragmentation. Bcl-2 over-expression both delays acidification and inhibits ICE-like protease activation. Generation of a rapid intracellular pH decrease, using the ionophore nigericin, induces ICE-like protease activation and apoptosis. ZVAD, a cell permeable inhibitor of ICE-like proteases, does not affect acidification but inhibits apoptosis induced by IL-3 removal or nigericin treatment. These data suggest that intracellular acidification triggers apoptosis by directly or indirectly activating ICE-like proteases.
Furlong
I J
IJ
CRC Centre for Cell and Molecular Biology, Chester Beatty Laboratories, London, UK.
Ascaso
R
R
Lopez Rivas
A
A
Collins
M K
MK
D017209:Apoptosis; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D053938:DNA Fragmentation; D004789:Enzyme Activation; D005434:Flow Cytometry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007377:Interleukin-3 / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
D007377:Interleukin-3; D011065:Poly(ADP-ribose) Polymerases; D003546:Cysteine Endopeptidases