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Platelet-Derived Growth Factor-BB Restores HIV Tat -Mediated Impairment of Neurogenesis: Role of GSK-3β/β-Catenin

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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.

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Acknowledgments

This work was supported by grants MH-068212, DA020392, DA023397 and DA024442 from the National Institutes of Health.

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The authors declare no competing financial interests.

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  1. Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center (DRC 8011), University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA

    Jie Chao, Lu Yang, Honghong Yao & Shilpa Buch

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  1. Jie Chao
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  2. Lu Yang
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  3. Honghong Yao
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Correspondence to Honghong Yao or Shilpa Buch.

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Jie Chao and Lu Yang are contributed equally to the work.

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Chao, J., Yang, L., Yao, H. et al. Platelet-Derived Growth Factor-BB Restores HIV Tat -Mediated Impairment of Neurogenesis: Role of GSK-3β/β-Catenin. J Neuroimmune Pharmacol 9, 259–268 (2014). https://doi.org/10.1007/s11481-013-9509-x

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