RASSF1C, an isoform of the tumor suppressor RASSF1A, promotes the accumulation of beta-catenin by interacting with betaTrCP.

Abstract

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 betaTrCP. Binding of RASSF1C to betaTrCP 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 betaTrCP; however, surprisingly, the association between RASSF1C and betaTrCP does not occur via the betaTrCP 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 betaTrCP-mediated degradation. Silencing of RASSF1A by small interfering RNA was sufficient for beta-catenin to accumulate, whereas silencing of both RASSF1A 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.

• Authors: Emilie Estrabaud, Irina Lassot, Guillaume Blot, Erwann Le Rouzic, Valérie Tanchou, Eric Quemeneur, Laurent Daviet, Florence Margottin-Goguet, Richard Benarous
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 3 Pg. 1054-61 (Feb 01 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17283138 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BTRC protein, human
• RASSF1 protein, human
• RNA, Small Interfering
• Tumor Suppressor Proteins
• beta Catenin
• beta-Transducin Repeat-Containing Proteins

Topics

• Amino Acid Motifs
• Cell Nucleus (metabolism)
• Cytoplasm (metabolism)
• Gene Silencing
• HeLa Cells
• Humans
• Protein Binding
• RNA, Small Interfering (genetics)
• Tumor Suppressor Proteins (genetics, metabolism)
• beta Catenin (antagonists & inhibitors, biosynthesis, genetics, metabolism)
• beta-Transducin Repeat-Containing Proteins (metabolism)