Calcineurin mediates acetylcholinesterase expression during calcium ionophore A23187-induced HeLa cell apoptosis.
We previously reported that acetylcholinesterase plays a critical role in apoptosis and its expression is regulated by Ca(2+) mobilization. In the present study, we show that activated calpain, a cytosolic calcium-activated cysteine protease, and calcineurin, a calcium-dependent protein phosphatase, regulate acetylcholinesterase expression during A23187-induced apoptosis. The calpain inhibitor, calpeptin, and the calcineurin inhibitors, FK506 and cyclosporine A, inhibited acetylcholinesterase expression at both mRNA and protein levels and suppressed the activity of the human acetylcholinesterase promoter. In contrast, overexpression of constitutively active calcineurin significantly activated the acetylcholinesterase promoter. Furthermore, we identify a role for the transcription factor NFAT (nuclear factor of activated T cells), a calcineurin target, in regulating the acetylcholinesterase promoter during ionophore-induced apoptosis. Overexpression of human NFATc3 and NFATc4 greatly increased the acetylcholinesterase promoter activity in HeLa cells treated with A23187. Overexpression of constitutive nuclear NFATc4 activated the acetylcholinesterase promoter independent of A23187, whereas overexpression of dominant-negative NFAT blocked A23187-induced acetylcholinesterase promoter activation. These results indicate that calcineurin mediates acetylcholinesterase expression during apoptosis.
Zhu
Hui
H
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Gao
Wei
W
Jiang
Hua
H
Wu
Jun
J
Shi
Yu-fang
YF
Zhang
Xue-Jun
XJ
D000110:Acetylcholinesterase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D000001:Calcimycin / Q000494:pharmacology*; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000037:antagonists & inhibitors; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007476:Ionophores / Q000494:pharmacology*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects
D065095:Calcineurin Inhibitors; D004791:Enzyme Inhibitors; D007476:Ionophores; D050778:NFATC Transcription Factors; D000001:Calcimycin; D000110:Acetylcholinesterase; D019703:Calcineurin; D002154:Calpain; D002118:Calcium