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J. Biol. Chem., Vol. 278, Issue 49, 48720-48726, December 5, 2003

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Calcium- and Proteasome-dependent Degradation of the JNK Scaffold Protein Islet-brain 1^*

Nathalie Allaman-Pillet, Joachim Størling¶, Anne Oberson, Raphael Roduit, Stéphanie Negri, Christelle Sauser, Pascal Nicod||, Jacques S. Beckmann, Daniel F. Schorderet, Thomas Mandrup-Poulsen¶**, and Christophe Bonny

From the Division of Medical Genetics and Unit of Molecular Genetics, ^||Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland, ^¶Steno Diabetes Center, DK-2820 Gentofte, Denmark, and ^**Department of Molecular Medicine, Karolinska Institute, SE-171 77 Stockholm, Sweden

In models of type 1 diabetes, cytokines induce pancreatic -cell death by apoptosis. This process seems to be facilitated by a reduction in the amount of the islet-brain 1/JNK interacting protein 1 (IB1/JIP1), a JNK-scaffold with an anti-apoptotic effect. A point mutation S59N at the N terminus of the scaffold, which segregates in diabetic patients, has the functional consequence of sensitizing cells to apoptotic stimuli. Neither the mechanisms leading to IB1/JIP1 down-regulation by cytokines nor the mechanisms leading to the decreased capacity of the S59N mutation to protect cells from apoptosis are understood. Here, we show that IB1/JIP1 stability is modulated by intracellular calcium. The effect of calcium depends upon JNK activation, which primes the scaffold for ubiquitination-mediated degradation via the proteasome machinery. Furthermore, we observe that the S59N mutation decreases IB1/JIP1 stability by sensitizing IB1/JIP1 to calcium- and proteasome-dependent degradation. These data indicate that calcium influx initiated by cytokines mediates ubiquitination and degradation of IB1/JIP1 and may, therefore, provide a link between calcium influx and JNK-mediated apoptosis in pancreatic -cells.

Received for publication, June 25, 2003 , and in revised form, September 12, 2003.

^* This work was supported by the Botnar Foundation, Danish Diabetes Association, Novo Nordisk A/S, Grant P-038/02 from the Gebert Rüf Stifstung Fundation, Juvenile Diabetes Research Foundation International Research Center Grant 4-2002-457, and Fonds National Suisse de la Recherche Scientifique Grant 3200-65139.01. 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.

To whom correspondence should be addressed: Unit of Molecular Genetics, Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland. Tel.: 41-21-314-3379; Fax: 41-21-314-3385; E-mail: Nathalie.Pillet{at}chuv.hospvd.ch.

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