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J. Biol. Chem., Vol. 281, Issue 10, 6413-6427, March 10, 2006

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AIFsh, a Novel Apoptosis-inducing Factor (AIF) Pro-apoptotic Isoform with Potential Pathological Relevance in Human Cancer^*

Cécile Delettre¹, Victor J. Yuste², Rana S. Moubarak³, Marlène Bras⁴, Jeanne-Claire Lesbordes-Brion, Stéphane Petres, Jacques Bellalou, and Santos A. Susin⁵

From the Apoptose et Système Immunitaire, CNRS-URA 1961 and Plateforme 5-Production de Protéines Recombinantes et d'Anticorps, Institut Pasteur, 25, rue du Dr. Roux, 75015 Paris, France

AIF is a main mediator of caspase-independent cell death. It is encoded by a single gene located on chromosome X, region q25–26 and A6 in humans and mice, respectively. Previous studies established that AIF codes for two isoforms of the protein, AIF and AIF-exB. Here, we identify a third AIF isoform resulting from an alternate transcriptional start site located at intron 9 of AIF. The resulting mRNA encodes a cytosolic protein that corresponds to the C-terminal domain of AIF (amino acids 353–613). We named this new isoform AIFshort (AIFsh). AIFsh overexpression in HeLa cells results in nuclear translocation and caspase-independent cell death. Once in the nucleus, AIFsh provokes the same effects than AIF, namely chromatin condensation and large scale (50 kb) DNA fragmentation. In contrast, these apoptogenic effects are not precluded by the AIF-inhibiting protein Hsp70. These findings identify AIFsh as a new pro-apoptotic isoform of AIF, and also reveal that the first N-terminal 352 amino acids of AIF are not required for its apoptotic activity. In addition, we demonstrate that AIFsh is strongly down-regulated in tumor cells derived from kidney, vulva, skin, thyroid, and pancreas, whereas, -irradiation treatment provokes AIFsh up-regulation. Overall, our results identify a novel member of the AIF-dependent pathway and shed new light on the role of caspase-independent cell death in tumor formation/suppression.

Received for publication, September 7, 2005 , and in revised form, December 15, 2005.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) DQ016496 [GenBank] and DQ016497 [GenBank] .

^* This work was supported by the Association pour la Recherche sur le Cancer (contract N° 4812), Fondation de France, Fondation pour la Recherche Médicale, Ligue Nationale contre le Cancer, and the Pasteur-Weizmann Scientific Council (to S. A. S). 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.

¹ Holds a postdoctoral fellowship from the Fondation de France.

² Supported by a Marie Curie Intra-European fellowship within the 6th European Community Framework Programme (contract MEIF-2003-501887).

³ Supported by a Ph.D. fellowship from Fondation Hariri.

⁴ Supported by a Ph.D. fellowship from MENRT.

⁵ To whom correspondence should be addressed: Apoptose et Système Immunitaire, CNRS-URA 1961, Institut Pasteur, 25 rue du Dr. Roux, 75015 Paris, France. Tel.: 33-1-40-61-31-84; Fax: 33-1-40-61-31-86; E-mail: susin{at}pasteur.fr.

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