Department of Neuroscience and Physiology, State University of New York-Upstate Medical University, Syracuse, New York.
Touro College of Osteopathic Medicine, Middletown, New York.
Alcohol Clin Exp Res. 2019 Apr;43(4):655-667. doi: 10.1111/acer.13976. Epub 2019 Mar 19.
Transforming growth factor (TGF) β1 and ethanol (EtOH) powerfully inhibit the proliferation, DNA repair, and survival of neural stem cells (NSCs). The present study tests the hypothesis that the EtOH-induced DNA damage response is mediated through p53 pathways and influenced by growth factor signals.
Cultures of nonimmortalized NSCs, NS-5 cells, were transfected with p53 siRNA, exposed to either the mitogenic fibroblast growth factor (FGF) 2 or antimitogenic TGFβ1, and to EtOH. Stage-specific cellular and genomic responses were examined.
p53 status, EtOH exposure, and growth factor significantly affected the expression of transcripts related to the DNA damage response (including those coding for excision repair proteins), mitotic promoters, and regulators of cell death via the tumor necrosis factor pathway. There were significant compensatory increases in p53 family members, p63 and p73, notably in regard to the regulation of cell cycle restriction and apoptosis. Treatment with p53 siRNA potentiated EtOH- and TGFβ1-induced changes in the numbers of proliferating NSCs and increased the proportion of NSCs expressing the apoptotic marker annexin V.
Thus, it appears that EtOH and TGFβ1 affect proliferation, DNA repair, and survival of NSCs via p53-mediated activities.
转化生长因子 (TGF) β1 和乙醇 (EtOH) 可强力抑制神经干细胞 (NSCs) 的增殖、DNA 修复和存活。本研究检验了 EtOH 诱导的 DNA 损伤反应是通过 p53 途径介导的，并且受到生长因子信号影响的假说。
非永生化 NSCs、NS-5 细胞培养物用 p53 siRNA 转染，分别用有丝分裂原成纤维细胞生长因子 (FGF) 2 或抗有丝分裂 TGFβ1 和 EtOH 处理，并检查细胞和基因组的阶段特异性反应。
p53 状态、EtOH 暴露和生长因子显著影响与 DNA 损伤反应（包括编码切除修复蛋白的那些）、有丝分裂启动子和通过肿瘤坏死因子途径调节细胞死亡的调节剂相关的转录物的表达。p53 家族成员 p63 和 p73 的表达明显增加，特别是在调节细胞周期限制和细胞凋亡方面。用 p53 siRNA 处理可增强 EtOH 和 TGFβ1 诱导的增殖 NSCs 数量的变化，并增加表达凋亡标志物膜联蛋白 V 的 NSCs 的比例。
因此，似乎 EtOH 和 TGFβ1 通过 p53 介导的活性影响 NSCs 的增殖、DNA 修复和存活。
