期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 29, 期 8, 页码 2264-2277出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01484-08
关键词
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资金
- Korean Ministry of Education, Science and Technology [M1063901, M20706000032]
- Chosun University Fund 2002
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 alpha 1 (GFR alpha 1), 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 GFR alpha 1 transcription through enhanced binding of NF-kappa B complexes to the GFR alpha 1 promoter. GFR alpha 1 levels correlate proportionally with Ape1/Ref-1 in cancer cells. The knockdown of endogenous Ape1/Ref-1 in pancreatic cancer cells markedly suppressed GFR alpha 1 expression and invasion in response to GNDF, while overexpression of GFR alpha 1 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 GFR alpha 1 expression may play important roles in pancreatic cancer progression and neuronal cell survival.
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