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Blood, 1 November 2003, Vol. 102, No. 9, pp. 3270-3279. Prepublished online as a Blood First Edition Paper on July 17, 2003; DOI 10.1182/blood-2003-03-0689. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-03-0689v1 2003-03-0689v2 102/9/3270    most recent 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zazzeroni, F. Articles by Franzoso, G. Search for Related Content PubMed PubMed Citation Articles by Zazzeroni, F. Articles by Franzoso, G. Related Collections Immunobiology Neoplasia Apoptosis Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Gadd45 mediates the protective effects of CD40 costimulation against Fas-induced apoptosis Francesca Zazzeroni, Salvatore Papa, Alicia Algeciras-Schimnich, Kellean Alvarez, Tiziana Melis, Concetta Bubici, Nathan Majewski, Nissim Hay, Enrico De Smaele, Marcus E. Peter, and Guido Franzoso From the Gwen Knapp Center for Lupus and Immunology Research, the Ben May Institute for Cancer Research, the Committees on Immunology and Cancer Biology, University of Chicago, IL; and the Department of Molecular Genetics, University of Illinois at Chicago. In B lymphocytes, induction of apoptosis or programmed cell death (PCD) by Fas (CD95/APO-1) is suppressed by the triggering of CD40. This suppression controls various aspects of the humoral immune response, including antibody affinity maturation. The opposing effects of these receptors are also crucial to B-cell homeostasis, autoimmune disease, and cancer. Cytoprotection by CD40 involves activation of protective genes mediated by NF-B transcription factors; however, its basis remains poorly understood. Here, we report that, in B cells, Gadd45 is induced by CD40 through a mechanism that requires NF-B and that this induction suppresses Fas-mediated killing. Importantly, up-regulation of Gadd45 by CD40 precedes Fas-induced caspase activation, as well as up-regulation of other NF-B–controlled inhibitors of apoptosis such as Bcl-xL and c-FLIPL. In the presence of Gadd45, the Fas-induced apoptotic cascade is halted at mitochondria. However, in contrast to Bcl-xL, Gadd45 is unable to hamper the "intrinsic" pathway for apoptosis and in fact appears to block Fas cytotoxicity herein by suppressing a mitochondria-targeting mechanism activated by this receptor. These findings identify Gadd45 as a critical mediator of the prosurvival response to CD40 stimulation and provide important new insights into the apoptotic mechanism that is triggered by Fas in B cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Matsuda, Y. Matsuda, and L. D'Adamio BRI3 Inhibits Amyloid Precursor Protein Processing in a Mechanistically Distinct Manner from Its Homologue Dementia Gene BRI2 J. Biol. Chem., June 5, 2009; 284(23): 15815 - 15825. [Abstract] [Full Text] [PDF] M. Travert, P. Ame-Thomas, C. Pangault, A. Morizot, O. Micheau, G. Semana, T. Lamy, T. Fest, K. Tarte, and T. Guillaudeux CD40 Ligand Protects from TRAIL-Induced Apoptosis in Follicular Lymphomas through NF-{kappa}B Activation and Up-Regulation of c-FLIP and Bcl-xL J. Immunol., July 15, 2008; 181(2): 1001 - 1011. [Abstract] [Full Text] [PDF] C. G. Pham, C. Bubici, F. Zazzeroni, J. R. Knabb, S. Papa, C. 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[Abstract] [Full Text] [PDF] A. Mittal, S. Papa, G. Franzoso, and R. Sen NF-{kappa}B-Dependent Regulation of the Timing of Activation-Induced Cell Death of T Lymphocytes J. Immunol., February 15, 2006; 176(4): 2183 - 2189. [Abstract] [Full Text] [PDF] G. B. Smith and E. S. Mocarski Contribution of GADD45 Family Members to Cell Death Suppression by Cellular Bcl-xL and Cytomegalovirus vMIA J. Virol., December 1, 2005; 79(23): 14923 - 14932. [Abstract] [Full Text] [PDF] S. Laxmanan, D. Datta, C. Geehan, D. M. Briscoe, and S. Pal CD40: A Mediator of Pro- and Anti-Inflammatory Signals in Renal Tubular Epithelial Cells J. Am. Soc. Nephrol., September 1, 2005; 16(9): 2714 - 2723. [Abstract] [Full Text] [PDF] N. Zhang, M. H. Ahsan, L. Zhu, L. C. Sambucetti, A. F. Purchio, and D. B. West NF-{kappa}B and Not the MAPK Signaling Pathway Regulates GADD45{beta} Expression during Acute Inflammation J. Biol. Chem., June 3, 2005; 280(22): 21400 - 21408. [Abstract] [Full Text] [PDF] P. E. Massa, X. Li, A. Hanidu, J. Siamas, M. Pariali, J. Pareja, A. G. Savitt, K. M. Catron, J. Li, and K. B. Marcu Gene Expression Profiling in Conjunction with Physiological Rescues of IKK{alpha}-null Cells with Wild Type or Mutant IKK{alpha} Reveals Distinct Classes of IKK{alpha}/NF-{kappa}B-dependent Genes J. Biol. Chem., April 8, 2005; 280(14): 14057 - 14069. [Abstract] [Full Text] [PDF] S. Papa, F. Zazzeroni, C. G. Pham, C. Bubici, and G. Franzoso Linking JNK signaling to NF-{kappa}B: a key to survival J. Cell Sci., October 15, 2004; 117(22): 5197 - 5208. [Abstract] [Full Text] [PDF] S. K. Mak and D. Kultz Gadd45 Proteins Induce G2/M Arrest and Modulate Apoptosis in Kidney Cells Exposed to Hyperosmotic Stress J. Biol. Chem., September 10, 2004; 279(37): 39075 - 39084. [Abstract] [Full Text] [PDF]

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