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J. Biol. Chem., Vol. 278, Issue 31, 28799-28811, August 1, 2003

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Identification of a Novel Krüppel-associated Box Domain Protein, Krim-1, That Interacts with c-Myc and Inhibits Its Oncogenic Activity^*

Hanjo Hennemann   ¶, Lothar Vassen  ¶, Christoph Geisen  ¶ ||, Martin Eilers ** and Tarik Möröy  

From the Institut für Zellbiologie (Tumorforschung), Universitätsklinikum Essen, Virchowstrasse 173, D-45122 Essen, Germany and ^**Institut für Molekularbiologie und Tumorforschung, Philipps Universität Marburg, D-35033 Marburg, Germany

We have used the Ras recruitment system to screen for proteins that interact with the N-terminally located transactivation domain of c-Myc. The Ras recruitment system is based on the activation of the mitogenic RAS signaling pathway in yeast by the mammalian GTPase Ha-Ras. This screen led to the identification of two novel nuclear proteins termed Krim-1A and Krim-1B that both contain an N-terminal KRAB box domain and 12 or 9 Krüppel C₂H₂ type zinc fingers at the C terminus, respectively. We found that sequences covering the Myc box II homology region are essential for the interaction with the Krim-1 proteins and that the second N-terminal zinc finger of Krim-1 is essential for Myc binding. Both Krim-1A and -B genes appear to be expressed ubiquitously with highest levels in spleen and lymph nodes. In particular, Krim-1B and, to a lesser extent, Krim-1A are able to decrease E-box-dependent transcriptional transactivation by c-Myc-Max complexes and also the ability of Myc to malignantly transform primary rat embryo fibroblasts, which is consistent with the functional repressive properties of their KRAB domains. The transcriptional corepressor Tif-1 is a binding partner for Krim-1 and stabilizes the protein. Our findings suggest that Myc-mediated functions can be negatively regulated by Krim-1, potentially in a complex with Tif-1.

Received for publication, July 18, 2002 , and in revised form, April 30, 2003.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant Mo 435-12/1, 12/2; the Fonds der Chemischen Industrie; and the Ifores program of the University of Essen, Fachbereich Medizin. 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.

Present address: caesar, center of advanced european studies and research, Friedensplatz 16, D-53111 Bonn, Germany.

^¶ The first three authors contributed equally to this work.

^|| Present address: The Burnham Institute, Signal Transduction Program, 10901 N. Torrey Pines Rd., La Jolla, CA 92037.

To whom correspondence should be addressed. Tel.: 49-201-723-3380; Fax: 49-201-723-5904; E-mail: moeroey{at}uni-essen.de.

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