Downregulation of extracellular signal-regulated kinase 1/2 activity by calmodulin KII modulates p21Cip1 levels and survival of immortalized lymphocytes from Alzheimer's disease patients
Downregulation of extracellular signal-regulated kinase 1/2 activity by calmodulin KII modulates p21Cip1 levels and survival of immortalized lymphocytes from Alzheimer's disease patients
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DOI：
10.1016/j.neurobiolaging.2012.10.014
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发表时间：
2013-04-01
影响因子：
4.2
通讯作者：
Martin-Requero, Angeles
中科院分区：
文献类型：
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作者：
Esteras, Noemi;Alquezar, Carolina;Martin-Requero, Angeles
以前，我们报道了钙/钙调素（CaM）依赖性损伤的阿尔茨海默病（AD）淋巴母细胞的血清剥夺诱导的细胞凋亡。这些细胞系显示下调细胞外信号调节激酶（ERK）1/2活性和p21的含量升高与对照细胞相比。本研究的目的是阐明AD细胞中p21含量的不同调节的分子机制。定量逆转录聚合酶链反应分析表明AD细胞中p21信使RNA（mRNA）水平增加。ERK 1/2抑制剂PD 98059可防止对照细胞死亡，并提高p21 mRNA和蛋白水平。钙调素拮抗剂，calmidazolium，和CaMKII抑制剂，KN-62，正常化AD淋巴母细胞的生存模式，通过增强ERK 1/2激活和降低p21 mRNA和蛋白水平。AD细胞中p21转录的上调似乎是叉头框O3 a（FOXO 3a）活性增加的结果，这是由于ERK 1/2介导的该转录因子的磷酸化减少，从而促进其核积累。AD细胞中的小鼠双微体2（MDM 2）蛋白水平相对于对照淋巴母细胞降低，表明FOXO 3a降解受损。(C)2013 Elsevier Inc. All rights reserved.
Previously, we reported a Ca2+/calmodulin (CaM)-dependent impairment of apoptosis induced by serum deprivation in Alzheimer's disease (AD) lymphoblasts. These cell lines showed downregulation of extracellular signal-regulated kinase (ERK)1/2 activity and elevated content of p21 compared with control cells. The aim of this study was to delineate the molecular mechanism underlying the distinct regulation of p21 content in AD cells. Quantitative reverse transcription polymerase chain reaction analysis demonstrated increased p21 messenger RNA (mRNA) levels in AD cells. The ERK1/2 inhibitor, PD98059, prevented death of control cells and enhanced p21 mRNA and protein levels. The CaM antagonist, calmidazolium, and the CaMKII inhibitor, KN-62, normalized the survival pattern of AD lymphoblasts by augmenting ERK1/2 activation and reducing p21 mRNA and protein levels. Upregulation of p21 transcription in AD cells appears to be the consequence of increased activity of forkhead box O3a (FOXO3a) as the result of diminished ERK1/2-mediated phosphorylation of this transcription factor, which in turn facilitates its nuclear accumulation. Murine double minute 2 (MDM2) protein levels were decreased in AD cells relative to control lymphoblasts, suggesting an impairment of FOXO3a degradation. (C) 2013 Elsevier Inc. All rights reserved.