title: Platelet-derived growth factor-BB restores HIV Tat -mediated impairment of neurogenesis: role of GSK-3β/β-catenin.
abstract: Our previous study demonstrated that platelet-derived growth factor-BB (PDGF-BB) increased the cell proliferation of primary rat neuronal progenitor cells (NPCs). However, whether PDGF-BB regulates neurogenesis in HIV-associated neurological disorder (HAND) remains largely unknown. In this study we demonstrated that pre-treatment of NPCs with PDGF-BB restored Tat-mediated impairment of cell proliferation via activation of p38 and JNK MAPK pathways. Moreover, treatment with PDGF-BB induced inactivation of glycogen synthase kinase-3β (GSK-3β), evidenced by its phosphorylation at Ser9, this effect was significantly inhibited by the p38 and JNK inhibitors. Level of nuclear β-catenin, the primary substrate of GSK-3β, was also concomitantly increased following PDGF-BB treatment, suggesting that PDGF-BB stimulates NPC proliferation via acting on GSK-3β to promote nuclear accumulation of β-catenin. This was further validated by gain and loss of function studies using cells transfected with either the wild type or mutant GSK-3β constructs. Together these data underpin the role of GSK-3β/β-catenin as a novel target that regulates NPC proliferation mediated by PDGF-BB with implications for therapeutic intervention for reversal of impaired neurogenesis inflicted by Tat.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center (DRC 8011), University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Chao
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.forename: Honghong
authors.initials: H
authors.lastname: Yao
authors.forename: Shilpa
authors.initials: S
authors.lastname: Buch
mesh_terms: D000818:Animals; D000077214:Becaplermin; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D015658:HIV Infections / Q000378:metabolism; D007150:Immunohistochemistry; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D055495:Neurogenesis / Q000502:physiology*; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: C495268:Ctnnb1 protein, rat; D020574:Proto-Oncogene Proteins c-sis; D051176:beta Catenin; D054322:tat Gene Products, Human Immunodeficiency Virus; D000077214:Becaplermin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3