RCAN1 Overexpression Exacerbates Calcium Overloading-Induced Neuronal Apoptosis

被引：36
作者：
Sun, Xiulian [1 ,4 ]
Wu, Yili [2 ,3 ,4 ]
Herculano, Bruno [4 ]
Song, Weihong [2 ,3 ,4 ]
机构：
[1] Shandong Univ, Qilu Hosp, Jinan 250100, Peoples R China
[2] Chongqing Med Univ, Childrens Hosp, Chongqing City Key Lab Translat Med Res Cognit De, Chongqing, Peoples R China
[3] Chongqing Med Univ, Childrens Hosp, Minist Educ, Key Lab Child Dev & Disorders, Chongqing, Peoples R China
[4] Univ British Columbia, Grad Program Neurosci, Brain Res Ctr, Dept Psychiat,Townsend Family Labs, Vancouver, BC V5Z 1M9, Canada
来源：
PLOS ONE | 2014年 / 9卷 / 04期
基金：
中国国家自然科学基金; 加拿大健康研究院;
关键词：
DOWN-SYNDROME; ALZHEIMERS-DISEASE; TRANSCRIPTION FACTORS; INHIBITS CALCINEURIN; OXIDATIVE STRESS; PROTEIN; DSCR1; EXPRESSION; GENE; PHOSPHORYLATION;
D O I：
10.1371/journal.pone.0095471
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
Down Syndrome (DS) patients develop characteristic Alzheimer's Disease (AD) neuropathology after their middle age. Prominent neuronal loss has been observed in the cortical regions of AD brains. However, the underlying mechanism leading to this neuronal loss in both DS and AD remains to be elucidated. Calcium overloading and oxidative stress have been implicated in AD pathogenesis. Two major isoforms of regulator of calcineurin 1 (RCAN1), RCAN1.1 and RCAN1.4, are detected in human brains. In this report we defined the transcriptional regulation of RCAN1.1 and RCAN1.4 by two alternative promoters. Calcium overloading upregulated RCAN1.4 expression by activating RCAN1.4 promoter through calcineurin-NFAT signaling pathway, thus forming a negative feedback loop in isoform 4 regulation. Furthermore, RCAN1.4 overexpression exacerbated calcium overloading-induced neuronal apoptosis, which was mediated by caspase-3 apoptotic pathway. Our results suggest that downregulating RCAN1.4 expression in neurons could be beneficial to AD patients.
引用
收藏
页数：8
相关论文
共 56 条
  • [1] Protein kinase-mediated regulation of calcineurin through the phosphorylation of modulatory calcineurin-interacting protein 1
    Abbasi, S
    Lee, JD
    Su, B
    Chen, X
    Alcon, JL
    Yang, JH
    Kellems, RE
    Xia, Y
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (12) : 7717 - 7726
  • [2] The essential role of MEKK3 signaling in angiotensin II-induced calcineurin/nuclear factor of activated T-cells activation
    Abbasi, S
    Su, B
    Kellems, RE
    Yang, JH
    Xia, Y
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (44) : 36737 - 36746
  • [3] Lipid peroxidation in neurodegeneration: new insights into Alzheimer's disease
    Arlt, S
    Beisiegel, U
    Kontush, A
    [J]. CURRENT OPINION IN LIPIDOLOGY, 2002, 13 (03) : 289 - 294
  • [4] NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21
    Arron, Joseph R.
    Winslow, Monte M.
    Polleri, Alberto
    Chang, Ching-Pin
    Wu, Hai
    Gao, Xin
    Neilson, Joel R.
    Chen, Lei
    Heit, Jeremy J.
    Kim, Seung K.
    Yamasaki, Nobuyuki
    Miyakawa, Tsuyoshi
    Francke, Uta
    Graef, Isabella A.
    Crabtree, Gerald R.
    [J]. NATURE, 2006, 441 (7093) : 595 - 600
  • [5] Baek KH, 2009, NATURE
  • [6] Coordination of growth and endoplasmic reticulum stress signaling by regulator of calcineurin 1 (RCAN1), a novel ATF6-inducible gene
    Belmont, Peter J.
    Tadimalla, Archana
    Chen, Wenqiong J.
    Martindale, Joshua J.
    Thuerauf, Donna J.
    Marcinko, Marie
    Gude, Natalie
    Sussman, Mark A.
    Glembotski, Christopher C.
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (20) : 14012 - 14021
  • [7] Overexpression of RCAN1 isoform 4 in mouse neurons leads to a moderate behavioral impairment
    Bhoiwala, Devang L.
    Koleilat, Issam
    Qian, Jiang
    Beyer, Barbara
    Hushmendy, Shazaan F.
    Mathew, Alex
    Bhoiwala, Dipti L.
    Ferland, Russell J.
    Crawford, Dana R.
    [J]. NEUROLOGICAL RESEARCH, 2013, 35 (01) : 79 - 89
  • [8] APOPTOSIS AND INCREASED GENERATION OF REACTIVE OXYGEN SPECIES IN DOWNS-SYNDROME NEURONS IN-VITRO
    BUSCIGLIO, J
    YANKNER, BA
    [J]. NATURE, 1995, 378 (6559) : 776 - 779
  • [9] Identification of a peptide fragment of DSCR1 that competitively inhibits calcineurin activity in vitro and in vivo
    Chan, B
    Greenan, G
    McKeon, F
    Ellenberger, T
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (37) : 13075 - 13080
  • [10] The Drosophila homolog of Down's syndrome critical region 1 gene regulates learning:: Implications for mental retardation
    Chang, KT
    Shi, YJ
    Min, KT
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (26) : 15794 - 15799
123456