The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Ape1/Ref-1 Stimulates GDNF/GFR ${\alpha}$ 1-mediated Downstream Signaling and Neuroblastoma Proliferation

  • Kang, Mi-Young (Department of Pharmacology, DNA Repair Center, Chosun University School of Medicine) ;
  • Kim, Kweon-Young (Department of Rehabilitation, Chosun University Hospital) ;
  • Yoon, Young (Department of Pharmacology, DNA Repair Center, Chosun University School of Medicine) ;
  • Kang, Yoon-Sung (Department of Pharmacology, DNA Repair Center, Chosun University School of Medicine) ;
  • Kim, Hong-Beum (Department of Pharmacology, DNA Repair Center, Chosun University School of Medicine) ;
  • Youn, Cha-Kyung (Department of Pharmacology, DNA Repair Center, Chosun University School of Medicine) ;
  • Kim, Dong-Hui (Department of Orthopaedic Surgery, Chosun University Hospital) ;
  • Kim, Mi-Hwa (Department of Pharmacology, DNA Repair Center, Chosun University School of Medicine)
  • Published : 2009.10.31
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Abstract

We previously reported that glial cell line-derived neurotropic factor (GDNF) receptor ${\alpha}$ 1 (GFR ${\alpha}$ 1) is a direct target of apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1). In the present study, we further analyzed the physiological roles of Ape1/Ref-1-induced GFR ${\alpha}$ 1 expression in Neuro2a mouse neuroblastoma cells. Ape1/Ref-1 expression caused the clustering of GFR ${\alpha}$ 1 immunoreactivity in lipid rafts in response to GDNF. We also found that Ret, a downstream target of GFR ${\alpha}$ 1, was functionally activated by GDNF in Ape1/Ref-1-expressing cells. Moreover, GDNF promoted the proliferation of Ape1/Ref-1-expressing Neuro2a cells. Furthermore, GFR ${\alpha}$ 1-specific RNA experiments demonstrated that the downregulation of GFR ${\alpha}$ 1 by siRNA in Ape1/Ref-1-expressing cells impaired the ability of GDNF to phosphorylate Akt and PLC ${\gamma}$-1 and to stimulate cellular proliferation. These results show an association between Ape1/Ref-1 and GDNF/GFR ${\alpha}$ signaling, and suggest a potential molecular mechanism for the involvement of Ape1/Ref-1 in neuronal proliferation.

Keywords

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