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KMID : 0811720090130050349
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Korean Journal of Physiology & Pharmacology
2009 Volume.13 No. 5 p.349 ~ p.356
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Ape1/Ref-1 Stimulates GDNF/GFR?1-mediated Downstream Signaling and Neuroblastoma Proliferation
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Kang Mi-Young
Kim Kweon-Young
Yoon Young
Kang Yoon-Sung
Kim Hong-Beum
Youn Cha-Kyung
Kim Dong-Hwi
Kim Mi-Hwa
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Abstract
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We previously reported that glial cell line-derived neurotropic factor (GDNF) receptor ?1 (GFR?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?1 expression in Neuro2a mouse neuroblastoma cells. Ape1/Ref-1 expression caused the clustering of GFR?1 immunoreactivity in lipid rafts in response to GDNF. We also found that Ret, a downstream target of GFR?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?1-specific RNA experiments demonstrated that the downregulation of GFR?1 by siRNA in Ape1/Ref-1-expressing cells impaired the ability of GDNF to phosphorylate Akt and PLC?-1 and to stimulate cellular proliferation. These results show an association between Ape1/Ref-1 and GDNF/GFR? signaling, and suggest a potential molecular mechanism for the involvement of Ape1/Ref-1 in neuronal proliferation.
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KEYWORD
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Ape1/Ref-1, GFR?1, GDNF, Lipid raft, Neuronal proliferation, Signal pathway
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