Korean J Physiol Pharmacol.  2009 Oct;13(5):349-356. 10.4196/kjpp.2009.13.5.349.

Ape1/Ref-1 Stimulates GDNF/GFR alpha1-mediated Downstream Signaling and Neuroblastoma Proliferation

Affiliations
  • 1Department of Pharmacology, DNA Repair Center, Chosun University School of Medicine, Gwangju 501-759, Korea. 9766m@hanmail.net
  • 2Department of Rehabilitation, Chosun University Hospital, Gwangju 501-717, Korea.
  • 3Department of Orthopaedic Surgery, Chosun University Hospital, Gwangju 501-717, Korea.

Abstract

We previously reported that glial cell line-derived neurotropic factor (GDNF) receptor alpha1 (GFR alpha1) 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 GFRalpha1 expression in Neuro2a mouse neuroblastoma cells. Ape1/Ref-1 expression caused the clustering of GFR alpha1 immunoreactivity in lipid rafts in response to GDNF. We also found that Ret, a downstream target of GFRalpha1, 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 alpha1-specific RNA experiments demonstrated that the downregulation of GFR alpha1 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.

Keyword

Ape1/Ref-1; GFR alpha1; GDNF; Lipid raft; Neuronal proliferation; Signal pathway
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