TY - JOUR
T1 - Platelet-derived growth factor-BB restores HIV Tat-mediated impairment of neurogenesis
T2 - Role of GSK-3β/β-catenin
AU - Chao, Jie
AU - Yang, Lu
AU - Yao, Honghong
AU - Buch, Shilpa
N1 - Funding Information:
Acknowledgments This work was supported by grants MH-068212, DA020392, DA023397 and DA024442 from the National Institutes of Health.
PY - 2014/3
Y1 - 2014/3
N2 - 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.
AB - 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.
KW - Beta-catenin
KW - GSK-3 beta
KW - HIV Tat
KW - Neuronal progenitor cell
KW - PDGF-BB
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U2 - 10.1007/s11481-013-9509-x
DO - 10.1007/s11481-013-9509-x
M3 - Article
C2 - 24248537
AN - SCOPUS:84896542702
SN - 1557-1890
VL - 9
SP - 259
EP - 268
JO - Journal of Neuroimmune Pharmacology
JF - Journal of Neuroimmune Pharmacology
IS - 2
ER -