Pro-apoptotic function of calsenilin/DREAM/KChIP3.
Apoptotic cell death and increased production of amyloid b peptide (Ab) are pathological features of Alzheimer's disease (AD), although the exact contribution of apoptosis to the pathogenesis of the disease remains unclear. Here we describe a novel pro-apoptotic function of calsenilin/DREAM/KChIP3. By antisense oligonucleotide-induced inhibition of calsenilin/DREAM/KChIP3 synthesis, apoptosis induced by Fas, Ca2+-ionophore, or thapsigargin is attenuated. Conversely, calsenilin/DREAM/KChIP3 expression induced the morphological and biochemical features of apoptosis, including cell shrinkage, DNA laddering, and caspase activation. Calsenilin/DREAM/KChIP3-induced apoptosis was suppressed by caspase inhibitor Z-VAD and by Bcl-XL, and was potentiated by increasing cytosolic Ca2+, expression of Swedish amyloid precursor protein mutant (APPSW) or presenilin 2 (PS2), but not by a PS2 deletion lacking its C-terminus (PS2/411stop). In addition, calsenilin/DREAM/KChIP3 expression increased Ab42 production in cells expressing APPsw, which was potentiated by PS2, but not by PS2/411stop, which suggests a role for apoptosis-associated Ab42 production of calsenilin/DREAM/KChIP3.
Jo
D G
DG
Department of Life Science, Kwangju Institute of Science and Technology, Puk-gu, Kwangju 500-712, Korea.
Kim
M J
MJ
Choi
Y H
YH
Kim
I K
IK
Song
Y H
YH
Woo
H N
HN
Chung
C W
CW
Jung
Y K
YK
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D051605:Kv Channel-Interacting Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma; D016376:Oligonucleotides, Antisense / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D053766:Presenilin-2; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D051020:bcl-X Protein
D000590:Amino Acid Chloromethyl Ketones; D016229:Amyloid beta-Peptides; C494811:BCL2L1 protein, human; C494813:Bcl2l1 protein, rat; D002135:Calcium-Binding Proteins; D015853:Cysteine Proteinase Inhibitors; C496749:KCNIP3 protein, human; C496760:Kcnip3 protein, rat; D051605:Kv Channel-Interacting Proteins; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053766:Presenilin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; C075222:amyloid beta-protein (1-42); D051020:bcl-X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D002118:Calcium