HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 3, 1777-1786, January 16, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/3/1777    most recent M305418200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Merluzzi, S. Articles by Pucillo, C. Search for Related Content PubMed PubMed Citation Articles by Merluzzi, S. Articles by Pucillo, C. Social Bookmarking                      What's this?

CD40 Stimulation Induces Pax5/BSAP and EBF Activation through a APE/Ref-1-dependent Redox Mechanism^*

Sonia Merluzzi, Massimo Moretti, Sandro Altamura, Patty Zwollo¶, Mikael Sigvardsson||, Gaetano Vitale, and Carlo Pucillo**

From the Dipartimento di Scienze e Tecnologie Biomediche, M.A.T.I. Center of Excellence P.le Kolbe 4, Università degli Studi di Udine, 33100 Udine, Italy, the ^¶Department of Biology, The College of William and Mary, Williamsburg, Virginia 23185, and the ^||Laboratory of Cellular Differentiation, Department of Stem Cell Biology, Lund University, S-221 84 Lund, Sweden

CD40 is a member of the growing tumor necrosis factor receptor family that has been shown to play important roles in T cell-mediated B lymphocyte activation. Ligation of B cell CD40 by CD154, mainly expressed on activated T cells, stimulates B cell proliferation, differentiation, isotype switching, up-regulation of surface molecules contributing to antigen presentation, development of the germinal center, and the humoral memory response. In this study we demonstrate that the redox factor APE/Ref-1 acts as a key signaling intermediate in response to CD40-mediated B cell activation. The transcription factors Pax5a or BSAP (B cell lineage-specific activator protein) and EBF (early B cell factor) are constitutively expressed in spleen B cells and CD40 cross-linking induces increases in Pax5a and EBF binding activity compared with nonstimulated B cells. We show that upon CD40 antibody-mediated cross-linking, APE/Ref-1 translocates from the cytoplasm to the nucleus of activated B cells, where it modulates the DNA binding activity of both Pax5a and EBF. Moreover, we show that the repression of APE/Ref-1 protein production is able to block CD40-mediated Pax5a activation. We also provide evidence that APE/Ref-1 can modulate the cooperative activation of the blk promoter operated by Pax5a and EBF and that APE/Ref-1 might directly regulate EBF functional activity. Finally, we show that the interaction between Pax5a and EBF enhances EBF binding activity to its consensus sequence, suggesting that Pax5a can physically interact with EBF and modulate its DNA binding activity.

Received for publication, May 23, 2003 , and in revised form, October 8, 2003.

^* This work was supported by grants from the Ministero della Ricerca Scientifica e Tecnologica (Cofin 2001), Ricerca Finalizzata Ministero della Sanità, ASI, AIRC, and Fondi Regione FVG L3/98. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed. Tel.: 39-0432-494340; Fax: 39-0432-494301; Email: cpucillo{at}makek.dstb.uniud.it.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				G.-M. Zou, M.-H. Luo, A. Reed, M. R. Kelley, and M. C. Yoder Ape1 regulates hematopoietic differentiation of embryonic stem cells through its redox functional domain Blood, March 1, 2007; 109(5): 1917 - 1922. [Abstract] [Full Text] [PDF]

				P. Oppezzo, G. Dumas, A. I. Lalanne, B. Payelle-Brogard, C. Magnac, O. Pritsch, G. Dighiero, and F. Vuillier Different isoforms of BSAP regulate expression of AID in normal and chronic lymphocytic leukemia B cells Blood, March 15, 2005; 105(6): 2495 - 2503. [Abstract] [Full Text] [PDF]