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Ape1/Ref-1 induces glial cell-derived neurotropic factor (GDNF) responsiveness by upregulating GDNF receptor alpha1
Mi-Hwa Kim1, Hong-Beum Kim, Samudra Acharya
1DNA Repair Research Center, Chosun University, Gwangju 501-759, South Korea.
Abstract:
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.
Insights
Apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) regulates glial cell-derived neurotrophic factor receptor alpha1 (GFRalpha1) expression. This mechanism impacts cancer cell invasion and neuronal survival in neurodegenerative diseases.
Area of Science:
- Molecular Biology
- Neuroscience
- Oncology
Background:
- Apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) is dysregulated in tumors and neurodegenerative diseases.
- The precise function of Ape1/Ref-1 in these conditions remains unclear.
- Glial cell-derived neurotrophic factor (GDNF) is crucial for neuronal survival and function.
Purpose of the Study:
- To elucidate the role of Ape1/Ref-1 in regulating GDNF signaling.
- To investigate the impact of Ape1/Ref-1 on GFRalpha1 expression and function.
- To determine the implications of Ape1/Ref-1-mediated GDNF responsiveness in cancer and neuronal cells.
Main Methods:
- Assessed Ape1/Ref-1's effect on GFRalpha1 expression in human fibroblasts.
- Investigated Ape1/Ref-1's mechanism of GFRalpha1 transcriptional induction via NF-kappaB.
- Utilized knockdown and overexpression strategies in pancreatic cancer and neuronal cells.
Main Results:
- Ape1/Ref-1 overexpression increased GFRalpha1 expression and GDNF responsiveness.
- Ape1/Ref-1 induced GFRalpha1 transcription by enhancing NF-kappaB binding to the GFRalpha1 promoter.
- Knockdown of Ape1/Ref-1 suppressed pancreatic cancer cell invasion, which was restored by GFRalpha1 overexpression.
- In neuronal cells, Ape1/Ref-1 promoted neurite outgrowth and protected against beta-amyloid and oxidative stress.
Conclusions:
- Ape1/Ref-1 is a novel regulator of GDNF responsiveness.
- Ape1/Ref-1-induced GFRalpha1 expression is implicated in pancreatic cancer progression.
- Ape1/Ref-1 plays a role in neuronal cell survival and protection.
