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Published on: October 4, 2016
p53-Mediated Activities in NS-5 Neural Stem Cells: Effects of Ethanol
Michael W Miller1,2,3
1Department of Neuroscience and Physiology, State University of New York-Upstate Medical University, Syracuse, New York.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
Thus, it appears that EtOH and TGFβ1 affect proliferation, DNA repair, and survival of NSCs via p53-mediated activities.
Insights
Ethanol and TGF-β1 inhibit neural stem cell (NSC) growth, DNA repair, and survival. This study shows these effects are mediated by p53 pathways, impacting cell proliferation and apoptosis.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Transforming growth factor (TGF) β1 and ethanol (EtOH) are known inhibitors of neural stem cell (NSC) proliferation, DNA repair, and survival.
- The precise mechanisms underlying EtOH-induced DNA damage and the influence of growth factors remain incompletely understood.
Purpose of the Study:
- To investigate the role of p53 pathways in mediating the effects of EtOH and growth factors on neural stem cells.
- To determine how EtOH-induced DNA damage response is modulated by specific growth factor signals.
Main Methods:
- Non-immortalized neural stem cells (NSCs) were utilized.
- Cells were transfected with p53 siRNA and exposed to fibroblast growth factor (FGF) 2, TGFβ1, and/or EtOH.
- Stage-specific cellular and genomic responses were analyzed.
Main Results:
- p53 status, EtOH exposure, and growth factors significantly altered DNA damage response transcripts, mitotic regulators, and cell death pathways.
- p53 family members, p63 and p73, showed compensatory increases, regulating cell cycle and apoptosis.
- p53 siRNA potentiated EtOH- and TGFβ1-induced reductions in NSC proliferation and increased apoptosis.
Conclusions:
- EtOH and TGFβ1 impact NSC proliferation, DNA repair, and survival through p53-mediated mechanisms.
- The p53 pathway is a critical mediator of cellular responses to EtOH and growth factors in neural stem cells.
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