Abstract
Platelet-derived growth factor (PDGF) has been implicated in promoting survival and proliferation of immature neurons, and even protecting neurons from gp120-induced cytotoxicity. However, the mechanisms involved in neuroprotection are not well understood. In the present study we demonstrate the role of phosphatidylinositol 3-kinase (PI3K)/Akt signaling in PDGF-mediated neuroprotection. Pharmacological inhibition of PI3K greatly reduced the ability of PDGF-BB to block gp120 IIIB-mediated apoptosis and cell death in human neuroblastoma cells. The role of Akt in PDGF-mediated protection was further corroborated using a dominant-negative mutant of Akt, which was able to block the protective effect of PDGF. We next sequentially examined the signals downstream of Akt in PDGF-mediated protection in human neuroblastoma cells. In cells pretreated with PDGF prior to gp120 there was increased phosphorylation of both GSK-3beta and Bad, an effect that was inhibited by PI3-kinase inhibitor. Nuclear translocation of NF-kappaB, which lies downstream of GSK-3beta, however, remained unaffected in cells treated with PDGF. In addition to inducing phosphorylation of Bad, PDGF-mediated protection also involved down-regulation of the proapoptotic protein Bax. Furthermore, PDGF-mediated protection also involved the inhibition of gp120-induced release of mitochondrial cytochrome C. Our findings thus underscore the roles of both PI3K/Akt and Bcl family pathways in PDGF-mediated neuroprotection.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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AIDS Dementia Complex / drug therapy
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AIDS Dementia Complex / metabolism
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AIDS Dementia Complex / physiopathology
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Active Transport, Cell Nucleus / drug effects
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Active Transport, Cell Nucleus / physiology
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Animals
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Apoptosis Regulatory Proteins / drug effects
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Apoptosis Regulatory Proteins / metabolism*
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Cell Line, Tumor
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Cells, Cultured
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Cytochromes c / metabolism
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Cytoprotection / drug effects
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Cytoprotection / physiology*
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Enzyme Inhibitors / pharmacology
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Glycogen Synthase Kinase 3 / drug effects
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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HIV Envelope Protein gp120 / antagonists & inhibitors
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HIV Envelope Protein gp120 / toxicity
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Humans
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NF-kappa B / metabolism
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Nerve Degeneration / drug therapy
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Nerve Degeneration / metabolism*
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Nerve Degeneration / physiopathology
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Neuroprotective Agents / metabolism*
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Neuroprotective Agents / pharmacology
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Phosphatidylinositol 3-Kinases / drug effects
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Phosphatidylinositol 3-Kinases / metabolism*
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Platelet-Derived Growth Factor / metabolism*
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Platelet-Derived Growth Factor / pharmacology
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Proto-Oncogene Proteins c-akt / drug effects
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Rats
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Rats, Sprague-Dawley
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Signal Transduction / drug effects
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Signal Transduction / physiology
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bcl-Associated Death Protein / drug effects
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bcl-Associated Death Protein / metabolism
Substances
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Apoptosis Regulatory Proteins
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Bad protein, rat
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Enzyme Inhibitors
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HIV Envelope Protein gp120
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NF-kappa B
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Neuroprotective Agents
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Platelet-Derived Growth Factor
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bcl-Associated Death Protein
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gp120 protein, Human immunodeficiency virus 1
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Cytochromes c
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Phosphatidylinositol 3-Kinases
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, rat
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3