Mechanisms of platelet-derived growth factor-mediated neuroprotection--implications in HIV dementia.
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.
Peng
Fuwang
F
Department of Molecular & Integrative Physiology, 5000 Wahl Hall East, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
Dhillon
Navneet K
NK
Yao
Honghong
H
Zhu
Xuhui
X
Williams
Rachel
R
Buch
Shilpa
S
D015526:AIDS Dementia Complex / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors / Q000633:toxicity; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051025:bcl-Associated Death Protein / Q000187:drug effects / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C494821:Bad protein, rat; D004791:Enzyme Inhibitors; D015699:HIV Envelope Protein gp120; D016328:NF-kappa B; D018696:Neuroprotective Agents; D010982:Platelet-Derived Growth Factor; D051025:bcl-Associated Death Protein; C514793:gp120 protein, Human immunodeficiency virus 1; D045304:Cytochromes c; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3