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J. Biol. Chem., Vol. 281, Issue 5, 2631-2638, February 3, 2006

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Central Role of the Scaffold Protein Tumor Necrosis Factor Receptor-associated Factor 2 in Regulating Endoplasmic Reticulum Stress-induced Apoptosis^*

Claudio Mauro¹, Elvira Crescenzi¹, Roberta De Mattia, Francesco Pacifico, Stefano Mellone, Salvatore Salzano, Cristiana de Luca, Luciano D'Adamio^¶||, Giuseppe Palumbo, Silvestro Formisano, Pasquale Vito^**, and Antonio Leonardi²

From the Dipartimento di Biologia e Patologia Cellulare e Molecolare and ^||Biochimica e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II," Via Pansini 5, 80131 Naples, Italy, the Istituto di Endocrinologia e Oncologia Sperimentale, CNR, Via Pansini 5, 80131 Naples, Italy, ^**Dipartimento di Scienze Biologiche e Ambientali, Università degli Studi del Sannio, Via Port'Arsa 11, 82100 Benevento, Italy, and the ^¶Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461

The endoplasmic reticulum represents the quality control site of the cell for folding and assembly of cargo proteins. A variety of conditions can alter the ability of the endoplasmic reticulum (ER) to properly fold proteins, thus resulting in ER stress. Cells respond to ER stress by activating different signal transduction pathways leading to increased transcription of chaperone genes, decreased protein synthesis, and eventually to apoptosis. In the present paper we analyzed the role that the adaptor protein tumor necrosis factor-receptor associated factor 2 (TRAF2) plays in regulating cellular responses to apoptotic stimuli from the endoplasmic reticulum. Mouse embryonic fibroblasts derived from TRAF2^-/- mice were more susceptible to apoptosis induced by ER stress than the wild type counterpart. This increased susceptibility to ER stress-induced apoptosis was because of an increased accumulation of reactive oxygen species following ER stress, and was abolished by the use of antioxidant. In addition, we demonstrated that the NF-B pathway protects cells from ER stress-induced apoptosis, controlling ROS accumulation. Our results underscore the involvement of TRAF2 in regulating ER stress responses and the role of NF-B in protecting cells from ER stress-induced apoptosis.

Received for publication, February 25, 2005 , and in revised form, October 17, 2005.

^* This work was supported by grants from the Associazione Italiana Ricerca sul Cancro, MIUR-FIRB RBNE0155LB, and Centro di Competenza GEAR. 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.

The on-line version of this article (available at http://www.jbc.org) contains Figs. A and B.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 39-0817463606; E-mail: leonardi{at}unina.it.

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