Destruction of β-catenin is regulated through phosphorylation-dependent interactions with the F box protein β-TrCP. A novel pathway for β-catenin degradation was discovered involving mammalian homologs of Drosophila Sina (Siah), which bind ubiquitin-conjugating enzymes, and Ebi, an F box protein that binds β-catenin independent of the phosphorylation sites recognized by β-TrCP. A series of protein interactions were identified in which Siah is physically linked to Ebi by association with a novel Sgt1 homolog SIP that binds Skp1, a central component of Skp1–Cullin–F box complexes. Expression of Siah is induced by p53, revealing a way of linking genotoxic injury to destruction of β-catenin, thus reducing activity of Tcf/LEF transcription factors and contributing to cell cycle arrest.