Involvement of a calcium-dependent dephosphorylation of BAD associated with the localization of Trpc-1 within lipid rafts in 7-ketocholesterol-induced THP-1 cell apoptosis.
7-Ketocholesterol is a component of oxidized LDL, which plays a central role in atherosclerosis. It is a potent inducer of cell death towards a wide number of cells involved in atherosclerosis. In this study, it is reported that 7-ketocholesterol treatment induces an increase of cytosolic-free Ca(2+) in THP-1 monocytic cells. This increase is correlated with the induction of cytotoxicity as suggested from experiments using the Ca(2+) channel blockers verapamil and nifedipine. This 7-ketocholesterol-induced apoptosis appears to be associated with the dephosphorylation of serine 75 and serine 99 of the proapoptotic protein Bcl-2 antagonist of cell death (BAD). We demonstrated that this dephosphorylation results mainly from the activation of calcium-dependent phosphatase calcineurin by the oxysterol-induced increase in Ca(2+). Moreover, this Ca(2+) increase appears related to the incorporation of 7-ketocholesterol into lipid raft domains of the plasma membrane, followed by the translocation of transient receptor potential calcium channel 1, a component of the store operated Ca(2+) entry channel, to rafts.
Berthier
A
A
Inserm U498 Métabolisme des lipoprotéines humaines et interactions vasculaires/IFR 100 Inserm, CHU/Hôpital du Bocage, BP77908, 21079 Dijon Cedex, France.
Lemaire-Ewing
S
S
Prunet
C
C
Monier
S
S
Athias
A
A
Bessède
G
G
Pais de Barros
J-P
JP
Laubriet
A
A
Gambert
P
P
Lizard
G
G
Néel
D
D
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D019254:Genes, bcl-2 / Q000502:physiology; D006801:Humans; D007653:Ketocholesterols / Q000494:pharmacology*; D021962:Membrane Microdomains / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism; D050052:TRPC Cation Channels; D014700:Verapamil / Q000494:pharmacology; D051025:bcl-Associated Death Protein
C494819:BAD protein, human; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002352:Carrier Proteins; D007653:Ketocholesterols; D050052:TRPC Cation Channels; D051025:bcl-Associated Death Protein; C096351:transient receptor potential cation channel, subfamily C, member 1; D012694:Serine; D014700:Verapamil; D019703:Calcineurin; D009543:Nifedipine; C003001:7-ketocholesterol; D002118:Calcium