Abstract
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.
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