RASSF1C, an isoform of the tumor suppressor RASSF1A, promotes the accumulation of β-catenin by interacting with βTrCP

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 beta TrCP. Binding of RASSF1C to beta TrCP involves serine 18 and serine 19 of the SS(18)GYXS(19) motif present in RASSF1C but not in RASSF1A. This motif is reminiscent of the canonical phosphorylation motif recognized by (dTrCP; however, surprisingly, the association between RASSF1C and TrCP does not occur via the beta TrCP substrate binding domain, the WD40 repeats. Overexpression of RASSF1C, but not of RASSF1A, resulted in accumulation and transcriptional activation of the beta-catenin oncogene, due to inhibition of its beta TrCP-mediated degradation. Silencing of RASSF1A by small interfering RNA was sufficient for (beta-catenin to accumulate, whereas silencing of both RASSFIA and RASSF1C had no effect. Thus, RASSF1A and RASSF1C have opposite effects on beta-catenin degradation. Our results suggest that RASSF1C expression in the absence of RASSF1A could play a role in tumorigenesis.