Ape1/Ref-1 induces glial cell-derived neurotropic factor (GDNF) responsiveness by upregulating GDNF receptor alpha1 expression.
Apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) dysregulation has been identified in several human tumors and in patients with a variety of neurodegenerative diseases. However, the function of Ape1/Ref-1 is unclear. We show here that Ape1/Ref-1 increases the expression of glial cell-derived neurotropic factor (GDNF) receptor alpha1 (GFRalpha1), a key receptor for GDNF. Expression of Ape1/Ref-1 led to an increase in the GDNF responsiveness in human fibroblast. Ape1/Ref-1 induced GFRalpha1 transcription through enhanced binding of NF-kappaB complexes to the GFRalpha1 promoter. GFRalpha1 levels correlate proportionally with Ape1/Ref-1 in cancer cells. The knockdown of endogenous Ape1/Ref-1 in pancreatic cancer cells markedly suppressed GFRalpha1 expression and invasion in response to GNDF, while overexpression of GFRalpha1 restored invasion. In neuronal cells, the Ape1/Ref-1-mediated increase in GDNF responsiveness not only stimulated neurite outgrowth but also protected the cells from beta-amyloid peptide and oxidative stress. Our results show that Ape1/Ref-1 is a novel physiological regulator of GDNF responsiveness, and they also suggest that Ape1/Ref-1-induced GFRalpha1 expression may play important roles in pancreatic cancer progression and neuronal cell survival.
Kim
Mi-Hwa
MH
DNA Repair Research Center, Chosun University, Gwangju 501-759, South Korea.
Kim
Hong-Beum
HB
Acharya
Samudra
S
Sohn
Hong-Moon
HM
Jun
Jae Yeoul
JY
Chang
In-Youb
IY
You
Ho Jin
HJ
D000818:Animals; D045744:Cell Line, Tumor; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000502:physiology*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000502:physiology*; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics*; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D016501:Neurites; D009474:Neurons / Q000166:cytology; D018384:Oxidative Stress; D010190:Pancreatic Neoplasms / Q000473:pathology; D011401:Promoter Regions, Genetic; D015854:Up-Regulation / Q000235:genetics*
C494987:GFRA1 protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D016328:NF-kappa B; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase