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J. Biol. Chem., Vol. 282, Issue 25, 18573-18583, June 22, 2007

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Tissue-specific Autophagy Alterations and Increased Tumorigenesis in Mice Deficient in Atg4C/Autophagin-3^*

Guillermo Mariño, Natalia Salvador-Montoliu, Antonio Fueyo, Erwin Knecht^¶, Noboru Mizushima^||, and Carlos López-Otín¹

From the Departamento de Bioquímica y Biología Molecular and Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain, ^¶Laboratorio de Biologia Celular, Centro de Investigacion Principe Felipe, 46013 Valencia, Spain, and ^||Department of Bioregulation and Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan, Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan, and SORST, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan

Atg4C/autophagin-3 is a member of a family of cysteine proteinases proposed to be involved in the processing and delipidation of the mammalian orthologues of yeast Atg8, an essential component of an ubiquitin-like modification system required for execution of autophagy. To date, the in vivo role of the different members of this family of proteinases remains unclear. To gain further insights into the functional relevance of Atg4 orthologues, we have generated mutant mice deficient in Atg4C/autophagin-3. These mice are viable and fertile and do not display any obvious abnormalities, indicating that they are able to develop the autophagic response required during the early neonatal period. However, Atg4C^-/--starved mice show a decreased autophagic activity in the diaphragm as assessed by immunoblotting studies and by fluorescence microscopic analysis of samples from Atg4C^-/- GFP-LC3 transgenic mice. In addition, animals deficient in Atg4C show an increased susceptibility to develop fibrosarcomas induced by chemical carcinogens. Based on these results, we propose that Atg4C is not essential for autophagy development under normal conditions but is required for a proper autophagic response under stressful conditions such as prolonged starvation. We also propose that this enzyme could play an in vivo role in events associated with tumor progression.

Received for publication, February 8, 2007 , and in revised form, March 21, 2007.

^* This work was supported by grants from Comisión Interministerial de Ciencia y Tecnología, Spain, Fundación Lilly, Fundación M. Botín, and European Union (Cancer Degradome-FP6). 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 Tel.: 34-985-104201; Fax: 34-985-103564; E-mail: clo{at}uniovi.es.

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