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Molecular and Cellular Biology, April 2009, p. 2264-2277, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01484-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Ape1/Ref-1 Induces Glial Cell-Derived Neurotropic Factor (GDNF) Responsiveness by Upregulating GDNF Receptor {alpha}1 Expression {triangledown} ,{ddagger}

Mi-Hwa Kim,1,{dagger} Hong-Beum Kim,1,{dagger} Samudra Acharya,1,2 Hong-Moon Sohn,3 Jae Yeoul Jun,1,4 In-Youb Chang,1,5* and Ho Jin You1,2*

DNA Repair Research Center, Chosun University, 375 Seosuk-dong, Gwangju 501-759, South Korea,1 Department of Pharmacology, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju 501-759, South Korea,2 Department of Orthopedic Surgery, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju 501-759, South Korea,3 Department of Physiology, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju 501-759, South Korea,4 Department of Anatomy, Chosun University School of Medicine, 375 Seosuk-dong, Gwangju 501-759, South Korea5

Received 22 September 2008/ Returned for modification 27 October 2008/ Accepted 22 January 2009

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 β-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.

* Corresponding author. Mailing address for Ho Jin You: DNA Repair Research Center and Department of Pharmacology, Bioengineering BD, 2F, Chosun University School of Medicine, 375 Seosuk-Dong, Gwangju 501-759, South Korea. Phone: 82-62-230-6337. Fax: 82-62-230-6586. E-mail: hjyou{at}chosun.ac.kr. Mailing address for In-Youb Chang: DNA Repair Research Center and Department of Anatomy, Bioengineering BD, 2F, Chosun University School of Medicine, 375 Seosuk-Dong, Gwangju 501-759, South Korea. Phone and fax: 82-62-230-6586. E-mail: hiyjang{at}chosun.ac.kr

{triangledown} Published ahead of print on 2 February 2009.

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} M.-H.K. and H.-B.K. contributed equally to this study.

Molecular and Cellular Biology, April 2009, p. 2264-2277, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01484-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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