Nucleic Acids Research

This Article Full Text Print PDF (330K) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Search for citing articles in: ISI Web of Science (48) Request Permissions Commercial Re-use Guidelines for Open Access NAR Content Google Scholar Articles by Tell, G. Articles by Pucillo, C. Search for Related Content PubMed PubMed Citation Articles by Tell, G. Articles by Pucillo, C. Social Bookmarking          What's this?

Nucleic Acids Research, 2000, Vol. 28, No. 5 1099-1105
© 2000 Oxford University Press

An ‘environment to nucleus’ signaling system operates in B lymphocytes: redox status modulates BSAP/Pax-5 activation through Ref-1 nuclear translocation

Gianluca Tell^1,2, Alessandro Zecca¹, Lucia Pellizzari¹, Paola Spessotto³, Alfonso Colombatti³, Mark R. Kelley⁴, Giuseppe Damante¹ and Carlo Pucillo^1,*

¹Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, P. le Kolbe 4, I-33100 Udine, Italy, ²Dipartimento di Biochimica, Biofisica e Chimica delle Macromolecole, Università di Trieste, Via Giorgieri 1, I-34127 Trieste, Italy, ³Divisione di Oncologia Sperimentale 2, Centro di Riferimento Oncologico di Aviano, I-33081 Aviano, Italy and ⁴Department of Pediatrics and Biochemistry and Molecular Biology, Herman B. Wells Center for Pediatric Research at Indiana University School of Medicine, Indianapolis, IN, USA

The Ref-1 (also called APE or HAP1) protein is a bifunctional enzyme impacting on a wide variety of important cellular functions. It acts as a major member of the DNA base excision repair pathway. Moreover, Ref-1 stimulates the DNA-binding activity of several transcription factors (TFs) through the reduction of highly reactive cysteine residues. Therefore, it represents a mechanism that regulates eukaryotic gene expression in a fast way. However, it has been demonstrated that external stimuli directly act on Ref-1 by increasing its expression levels, a time-consuming mechanism representing a paradox in terms of rapidity of TF regulation. In this paper we demonstrate that this is only an apparent paradox. Exposure of B lymphocytes to H₂O₂ induced a rapid and sustained increase in Ref-1 protein levels in the nucleus as evaluated by both western blot analysis and by pulse–chase experiments. A time course, two color in situ immunocytochemistry indicated that the up-regulation of Ref-1 in the nucleus at <30 min was primarily the consequence of translocation of its cytoplasmic form. This early nuclear accumulation is effective in modulating the DNA-binding activity of the B cell-specific activator protein BSAP/Pax-5. In fact, EMSA experiments demonstrate that a transient interaction with Ref-1 up-regulates the DNA-binding activity of BSAP/Pax-5. Moreover, in a co-transfection experiment, Ref-1 increased the BSAP/Pax-5 activating effect on an oligomerized BSAP/Pax-5 binding site of the CD19 promoter by 5- to 8-fold. Thus, Ref-1 mediates its effect by up-regulating the DNA-binding activity of BSAP/Pax-5, accounting for a new and fast outside/inside pathway of signaling in B cells.

^* To whom correspondence should be addressed. Tel: +39 0432 494340; Fax: +39 0432 494301; Email: cpucillo@makek.dstb.uniud.it

CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				L. M. Griffiths, D. Swartzlander, K. L. Meadows, K. D. Wilkinson, A. H. Corbett, and P. W. Doetsch Dynamic Compartmentalization of Base Excision Repair Proteins in Response to Nuclear and Mitochondrial Oxidative Stress Mol. Cell. Biol., February 1, 2009; 29(3): 794 - 807. [Abstract] [Full Text] [PDF]

				Z. Yang, S. Yang, B. J. Misner, R. Chiu, F. Liu, and F. L. Meyskens Jr. Nitric oxide initiates progression of human melanoma via a feedback loop mediated by apurinic/apyrimidinic endonuclease-1/redox factor-1, which is inhibited by resveratrol Mol. Cancer Ther., December 1, 2008; 7(12): 3751 - 3760. [Abstract] [Full Text] [PDF]

				K. Ando, S. Hirao, Y. Kabe, Y. Ogura, I. Sato, Y. Yamaguchi, T. Wada, and H. Handa A new APE1/Ref-1-dependent pathway leading to reduction of NF-{kappa}B and AP-1, and activation of their DNA-binding activity Nucleic Acids Res., August 1, 2008; 36(13): 4327 - 4336. [Abstract] [Full Text] [PDF]

				H. Fung, P. Liu, and B. Demple ATF4-Dependent Oxidative Induction of the DNA Repair Enzyme Ape1 Counteracts Arsenite Cytotoxicity and Suppresses Arsenite-Mediated Mutagenesis Mol. Cell. Biol., December 15, 2007; 27(24): 8834 - 8847. [Abstract] [Full Text] [PDF]

				K. Iwasaki, E. L. MacKenzie, K. Hailemariam, K. Sakamoto, and Y. Tsuji Hemin-Mediated Regulation of an Antioxidant-Responsive Element of the Human Ferritin H Gene and Role of Ref-1 during Erythroid Differentiation of K562 Cells. Mol. Cell. Biol., April 1, 2006; 26(7): 2845 - 2856. [Abstract] [Full Text] [PDF]

				A. Pines, L. Perrone, N. Bivi, M. Romanello, G. Damante, M. Gulisano, M. R. Kelley, F. Quadrifoglio, and G. Tell Activation of APE1/Ref-1 is dependent on reactive oxygen species generated after purinergic receptor stimulation by ATP Nucleic Acids Res., August 2, 2005; 33(14): 4379 - 4394. [Abstract] [Full Text] [PDF]

				K.-Y. Chyu, P. C Dimayuga, X. Zhao, J. Nilsson, P. K Shah, and B. Cercek Altered AP-1/Ref-1 redox pathway and reduced proliferative response in iNOS-deficient vascular smooth muscle cells Vascular Medicine, August 1, 2004; 9(3): 177 - 183. [Abstract] [PDF]

				D. Wang, M. Luo, and M. R. Kelley Human apurinic endonuclease 1 (APE1) expression and prognostic significance in osteosarcoma: Enhanced sensitivity of osteosarcoma to DNA damaging agents using silencing RNA APE1 expression inhibition Mol. Cancer Ther., June 1, 2004; 3(6): 679 - 686. [Abstract] [Full Text] [PDF]

				S. Merluzzi, M. Moretti, S. Altamura, P. Zwollo, M. Sigvardsson, G. Vitale, and C. Pucillo CD40 Stimulation Induces Pax5/BSAP and EBF Activation through a APE/Ref-1-dependent Redox Mechanism J. Biol. Chem., January 16, 2004; 279(3): 1777 - 1786. [Abstract] [Full Text] [PDF]

				T. He, N. L. Weintraub, P. C. Goswami, P. Chatterjee, D. M. Flaherty, F. E. Domann, and L. W. Oberley Redox factor-1 contributes to the regulation of progression from G0/G1 to S by PDGF in vascular smooth muscle cells Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H804 - H812. [Abstract] [Full Text] [PDF]

				J. M. Ordway, D. Eberhart, and T. Curran Cysteine 64 of Ref-1 Is Not Essential for Redox Regulation of AP-1 DNA Binding Mol. Cell. Biol., June 15, 2003; 23(12): 4257 - 4266. [Abstract] [Full Text] [PDF]

				M. R. Kelley, Y. W. Kow, and D. M. Wilson III Disparity between DNA Base Excision Repair in Yeast and Mammals: Translational Implications Cancer Res., February 1, 2003; 63(3): 549 - 554. [Abstract] [Full Text] [PDF]

				H. Skala-Rubinson, J. Vinh, V. Labas, A. Kahn, and F. P. D. Tuy Novel Target Sequences for Pax-6 in the Brain-specific Activating Regions of the Rat Aldolase C Gene J. Biol. Chem., November 27, 2002; 277(49): 47190 - 47196. [Abstract] [Full Text] [PDF]

				D. M. Flaherty, M. M. Monick, A. B. Carter, M. W. Peterson, and G. W. Hunninghake Oxidant-Mediated Increases in Redox Factor-1 Nuclear Protein and Activator Protein-1 DNA Binding in Asbestos-Treated Macrophages J. Immunol., June 1, 2002; 168(11): 5675 - 5681. [Abstract] [Full Text] [PDF]

				G. Tell, A. Pines, I. Paron, A. D'Elia, A. Bisca, M. R. Kelley, G. Manzini, and G. Damante Redox Effector Factor-1 Regulates the Activity of Thyroid Transcription Factor 1 by Controlling the Redox State of the N Transcriptional Activation Domain J. Biol. Chem., April 19, 2002; 277(17): 14564 - 14574. [Abstract] [Full Text] [PDF]

				D. M. Flaherty, M. M. Monick, and G. W. Hunninghake AP Endonucleases and the Many Functions of Ref-1 Am. J. Respir. Cell Mol. Biol., December 1, 2001; 25(6): 664 - 667. [Full Text] [PDF]

				M. Lowen, G. Scott, and P. Zwollo Functional Analyses of Two Alternative Isoforms of the Transcription Factor Pax-5 J. Biol. Chem., November 2, 2001; 276(45): 42565 - 42574. [Abstract] [Full Text] [PDF]

				M. R. Kelley, L. Cheng, R. Foster, R. Tritt, J. Jiang, J. Broshears, and M. Koch Elevated and Altered Expression of the Multifunctional DNA Base Excision Repair and Redox Enzyme Ape1/ref-1 in Prostate Cancer Clin. Cancer Res., April 1, 2001; 7(4): 824 - 830. [Abstract] [Full Text]

				K. A. Robertson, H. A. Bullock, Y. Xu, R. Tritt, E. Zimmerman, T. M. Ulbright, R. S. Foster, L. H. Einhorn, and M. R. Kelley Altered Expression of Ape1/ref-1 in Germ Cell Tumors and Overexpression in NT2 Cells Confers Resistance to Bleomycin and Radiation Cancer Res., March 1, 2001; 61(5): 2220 - 2225. [Abstract] [Full Text]

				J. Anspach, G. Poulsen, I. Kaattari, R. Pollock, and P. Zwollo Reduction in DNA Binding Activity of the Transcription Factor Pax-5a in B Lymphocytes of Aged Mice J. Immunol., February 15, 2001; 166(4): 2617 - 2626. [Abstract] [Full Text] [PDF]

Online ISSN 1362-4962 - Print ISSN 0305-1048

Copyright © 2009 Oxford University Press

Oxford Journals Oxford University Press

• Site Map
• Privacy Policy
• Frequently Asked Questions

Other Oxford University Press sites: Oxford University Press Oxford Journals China Oxford Journals Japan American National Biography Booksellers' Information Service Children's Fiction and Poetry Children's Reference Corporate & Special Sales Dictionaries Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks Humanities International Education Unit Law Medicine Music Online Products Oxford English Dictionary Reference Rights and Permissions Science School Books Social Sciences Very Short Introductions World's Classics