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RASSF1C, an Isoform of the Tumor Suppressor RASSF1A, Promotes the Accumulation of ß-Catenin by Interacting with ßTrCP

¹ Institut Cochin, Département Maladies Infectieuses; Institut National de la Sante et de la Recherche Medicale, U567; Centre National de la Recherche Scientifique, UMR 8104; Université Paris Descartes, Faculté de Médecine René Descartes, UMR-S 8104; ² Hybrigenics, Paris, France; and ³ CEA Valrhô, DSV, DIEP, SBTN, BP 17171, Bagnols sur Cèze cedex, France

Requests for reprints: Florence Margottin-Goguet, Department of Infectious Diseases, Institut National de la Sante et de la Recherche Medicale, 27, rue du Faubourg Saint Jacques, Bat G Roussy, 5eme etage, 75014 Paris, France. Phone: 33-1-40-51-66-16; Fax: 33-1-40-51-65-70; E-mail: margottin-goguet{at}cochin.inserm.fr or Richard Benarous, Department of Infectious Diseases, Institut National de la Sante et de la Recherche Medicale, 27, rue du Faubourg Saint Jacques, Bat G Roussy, 5eme etage, 75014 Paris, France. Phone: 33-1-40-51-65-71; Fax: 33-1-40-51-65-70; E-mail: benarous{at}cochin.inserm.fr.

The Ras-association domain family 1 (RASSF1) gene has seven different isoforms; isoform A is a tumor-suppressor gene (RASSF1A). The promoter of RASSF1A is inactivated in many cancers, whereas the expression of another major isoform, RASSF1C, is not affected. Here, we show that RASSF1C, but not RASSF1A, interacts with ßTrCP. Binding of RASSF1C to ßTrCP involves serine 18 and serine 19 of the SS₁₈GYXS₁₉ motif present in RASSF1C but not in RASSF1A. This motif is reminiscent of the canonical phosphorylation motif recognized by ßTrCP; however, surprisingly, the association between RASSF1C and ßTrCP does not occur via the ßTrCP substrate binding domain, the WD40 repeats. Overexpression of RASSF1C, but not of RASSF1A, resulted in accumulation and transcriptional activation of the ß-catenin oncogene, due to inhibition of its ßTrCP-mediated degradation. Silencing of RASSF1A by small interfering RNA was sufficient for ß-catenin to accumulate, whereas silencing of both RASSF1A and RASSF1C had no effect. Thus, RASSF1A and RASSF1C have opposite effects on ß-catenin degradation. Our results suggest that RASSF1C expression in the absence of RASSF1A could play a role in tumorigenesis. [Cancer Res 2007;67(3):1054–61]

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