Activation of GSK3b by Sirt2 Is Required for Early Lineage Commitment of Mouse Embryonic Stem Cell
PLOS ONE
Authors: Si, Xiaoxing; Chen, Wen; Guo, Xudong; Chen, Long; Wang, Guiying; Xu, Yanxin; Kang, Jiuhong
Abstract
Sirt2, a member of the NAD(+)-dependent protein deacetylase family, is increasingly recognized as a critical regulator of the cell cycle, cellular necrosis and cytoskeleton organization. However, its role in embryonic stem cells (ESCs) remains unclear. Here we demonstrate that Sirt2 is up-regulated during RA (retinoic acid)-induced and embryoid body (EB) differentiation of mouse ESCs. Using lentivirus-mediated shRNA methods, we found that knockdown of Sirt2 compromises the differentiation of mouse ESCs into ectoderm while promoting mesoderm and endoderm differentiation. Knockdown of Sirt2 expression also leads to the activation of GSK3 beta through decreased phosphorylation of the serine at position 9 (Ser9) but not tyrosine at position 216 (Tyr216). Moreover, the constitutive activation of GSK3 beta during EB differentiation mimics the effect of Sirt2 knockdown, while down-regulation of GSK3 beta rescues the effect of Sirt2 knockdown on differentiation. In contrast to the effect on lineage differentiation, Sirt2 knockdown and GSK3 beta up-regulation do not change the self-renewal state of mouse ESCs. Overall, our report reveals a new function for Sirt2 in regulating the proper lineage commitment of mouse ESCs.
GSK3 beta Reduces Risk of Sporadic Parkinson's Disease in Ethnic Chinese
AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS
Authors: Zhao, Dong-Mei; Li, Nan-Nan; Zhang, Jin-Hong; Chang, Xue-Li; Mao, Xue-Ye; Liao, Qiao; Tan, Eng-King; Peng, Rong
Abstract
Genetic variability of glycogen synthase kinase-3 beta (GSK3 beta) may be linked to Parkinson's disease (PD). Its role in ethnic Chinese population is still unclear. We examined the association between GSK3 beta variation and PD in a Han Chinese population from mainland China. Using a case-control methodology, we genotyped the single nucleotide polymorphism (SNP) in GSK3 beta (rs334558) to investigate the association with risk of PD. A total of 1,280 ethnic Han Chinese study subjects comprising 761 sporadic PD patients and 519 controls were recruited. The T allele of a promoter SNP rs334558 was found to reduce the risk of PD (OR = 0.82, 95% CI: 0.696-0.960, P = 0.014). Patients with CT + TT genotypes have a reduced risk of PD compared to those with CC genotype (OR = 0.61, 95% CI: 0.477-0.776, P = 6.09E-5). In addition, we demonstrated that CT + TT subjects cannot be distinguished from CC subjects based on their clinical features. Our data suggest that rs334558 variant in GSK3 beta reduces the risk of PD in a Han Chinese population from mainland China. Further studies of large series of subjects are necessary to fully elucidate the true role of GSK3 beta in PD. (C) 2012 Wiley Periodicals, Inc.