Jo D G, Kim M J, Choi Y H, Kim I K, Song Y H, Woo H N, Chung C W, Jung Y K
Department of Life Science, Kwangju Institute of Science and Technology, Puk-gu, Kwangju 500-712, Korea.
FASEB J. 2001 Mar;15(3):589-91. doi: 10.1096/fj.00-0541fje. Epub 2001 Jan 19.
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.
凋亡性细胞死亡以及淀粉样β肽（Aβ）生成增加是阿尔茨海默病（AD）的病理特征，尽管凋亡在该疾病发病机制中的具体作用仍不清楚。在此，我们描述了钙调神经磷酸酶结合蛋白/DREAM/KChIP3一种新的促凋亡功能。通过反义寡核苷酸诱导抑制钙调神经磷酸酶结合蛋白/DREAM/KChIP3的合成，可减弱由Fas、钙离子载体或毒胡萝卜素诱导的凋亡。相反，钙调神经磷酸酶结合蛋白/DREAM/KChIP3的表达诱导了凋亡的形态学和生化特征，包括细胞皱缩、DNA梯状条带形成以及半胱天冬酶激活。钙调神经磷酸酶结合蛋白/DREAM/KChIP3诱导的凋亡被半胱天冬酶抑制剂Z-VAD和Bcl-XL抑制，并通过增加胞质钙离子、瑞典淀粉样前体蛋白突变体（APPSW）或早老素2（PS2）的表达而增强，但不被缺乏其C末端的PS2缺失体（PS2/411stop）增强。此外，钙调神经磷酸酶结合蛋白/DREAM/KChIP3的表达增加了表达APPsw细胞中Aβ42的生成，PS2可增强此作用，但PS2/411stop则不能，这表明钙调神经磷酸酶结合蛋白/DREAM/KChIP3在与凋亡相关的Aβ42生成中发挥作用。
