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J. Biol. Chem., Vol. 281, Issue 26, 17779-17788, June 30, 2006

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Identification of Proteins Cleaved Downstream of Caspase Activation in Monocytes Undergoing Macrophage Differentiation^*

Séverine Cathelin^¶, Cédric Rébé^¶1, Lamya Haddaoui^||**, Nicolas Simioni^¶, Frédérique Verdier^||**, Michaëla Fontenay^||**, Sophie Launay^¶2, Patrick Mayeux^||**, and Eric Solary^¶3

From the Inserm UMR 517, Dijon F-21079, France, IFR100, University of Burgundy, Dijon F-21079, France, ^¶Centre Hospitalier Régional Universitaire Dijon, Hospital Le Bocage, Hematology Department, Dijon F-21034, France, ^||Inserm U567, Hematology Department, Paris F-75014, France, ^**CNRS UMR 8104, Paris F-75014, France, and René Descartes University, Paris F-75014, France

We have shown previously that caspases were specifically involved in the differentiation of peripheral blood monocytes into macrophages while not required for monocyte differentiation into dendritic cells. To identify caspase targets in monocytes undergoing macrophagic differentiation, we used the human monocytic leukemic cell line U937, whose macrophagic differentiation induced by exposure to 12-O-tetradecanoylphorbol 13-acetate (TPA) can be prevented by expression of the baculovirus caspase-inhibitory protein p35. A comparative two-dimensional gel proteomic analysis of empty vector- and p35-transfected cells after 12 h of exposure to 20 nM TPA, followed by mass spectrometry analysis, identified 38 differentially expressed proteins. Those overexpressed in p35-expressing cells (n = 16) were all full-length, whereas half of those overexpressed in control cells (n = 22) were N- or C-terminal cleavage fragments. The cleavage or degradation of seven of these proteins was confirmed in peripheral blood monocytes undergoing macrophage colony-stimulating factor-induced macrophagic differentiation. In U937 cells exposed to TPA, these proteolytic events can be inhibited by expression of a caspase-8 dominant negative mutant or the cowpox virus CrmA caspase inhibitor. These cleavages provide new insights to analyze the role of caspases in this specific differentiation program.

Received for publication, January 18, 2006 , and in revised form, April 19, 2006.

^* This work was supported by a grant from the Ligue Nationale Contre le Cancer (Equipe Labelisee). 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 one supplemental figure.

¹ Supported by the Association pour la Recherche sur le Cancer.

² Supported by the Ligue Nationale Contre le Cancer.

³ To whom correspondence should be sent: INSERM UMR517, IFR100, Faculty of Medicine, 7 Boulevard Jeanne d'Arc, 21079 Dijon Cedex, France. Tel.: 33-3-80-39-33-52; Fax: 33-3-80-39-34-34; E-mail: esolary{at}u-bourgogne.fr.

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