Nerve growth factor potentiates p53 DNA binding but inhibits nitric oxide-induced apoptosis in neuronal PC12 cells.
NGF is recognized for its role in neuronal differentiation and maintenance. Differentiation of PC12 cells by NGF involves p53, a transcription factor that controls growth arrest and apoptosis. We investigated NGF influence over p53 activity during NO-induced apoptosis by sodium nitroprusside in differentiated and mitotic PC12 cells. NGF-differentiation produced increased p53 levels, nuclear localization and sequence-specific DNA binding. Apoptosis in mitotic cells also produced these events but the accompanying activation of caspases 1-10 and mitochondrial depolarization were inhibited during NGF differentiation and could be reversed in p53-silenced cells. Transcriptional regulation of PUMA and survivin expression were not inhibited by NGF, although NO-induced mitochondrial depolarization was dependent upon de novo gene transcription and only occurred in mitotic cells. We conclude that NGF mediates prosurvival signaling by increasing factors such as Bcl-2 and p21(Waf1/Cip1) without altering p53 transcriptional activity to inhibit mitochondrial depolarization, caspase activation and apoptosis.
Brynczka
Christopher
C
National Center for Toxicogenomics, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, Research Triangle Park, NC 27709, USA.
Merrick
Bruce Alex
BA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D004357:Drug Synergism; D004789:Enzyme Activation; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D020932:Nerve Growth Factor / Q000502:physiology*; D009569:Nitric Oxide / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D009599:Nitroprusside; D009569:Nitric Oxide; D004247:DNA; D020932:Nerve Growth Factor; D020169:Caspases