title: Regulation of RCAN1 translation and its role in oxidative stress-induced apoptosis.
abstract: Abnormal expression of regulator of calcineurin 1 (RCAN1) has been implicated in Alzheimer's disease (AD) and Down's syndrome (DS). There are two major isoforms of RCAN1, isoforms 1 and 4. RCAN1 isoform 1 is predominantly expressed in the brain, particularly in neurons. In this report, we showed that there are two translation start codons in RCAN1 exon 1 serving as a functional translation initiation site to generate a longer 41-kDa isoform 1 (RCAN1.1L) and a shorter 31-kDa isoform 1 (RCAN1.1S). The first translation initiation site has higher translation efficiency than the downstream second one, and the translation initiation of two AUG sites is by a Cap-dependent mechanism. Short-term expression of RCAN1.1L protected SH-SY5Y cells from oxidative stress-induced apoptosis by inhibiting caspase-3 activation. However, long-term accumulation of RCAN1.1L in SH-SY5Y cells promoted oxidative stress-induced apoptosis via caspase-3 activation, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay showed that the apoptosis ratio was increased to 499.03 ± 47.56% in SH-1.1L cells compared with 283.93 ± 28.66% in control cells. Furthermore, we found that RCAN1.1L is significantly elevated in the AD brains and patients with DS. RCAN1.1S is expressed at a low level in both human cells and brain tissues. Our results defined the regulatory mechanism underlying RCAN1 expression and the roles of RCAN1.1 in oxidative stress-induced neurodegeneration in AD and DS pathogenesis.
authors.affiliation: Chongqing City Key Lab of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Yili
authors.initials: Y
authors.lastname: Wu
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D018387:Codon, Initiator; D004268:DNA-Binding Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D009124:Muscle Proteins / Q000235:genetics*; D018384:Oxidative Stress; D014176:Protein Biosynthesis
chemical_list: D018387:Codon, Initiator; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C108612:RCAN1 protein, human