β-TrCP1-variant 4, a novel splice variant of β-TrCP1, is a negative regulator of β-TrCP1-variant 1 in β-catenin degradation.

β-transducin repeats-containing protein-1 (β-TrCP1) serves as the substrate recognition subunit for SCF E3 ubiquitin ligases, which specifically ubiquitinate phosphorylated substrates. Three variants of β-TrCP1 are known and act as homodimer or heterodimer complexes. Here, we identified a novel full-sequenced variant, β-TrCP1-variant 4, which harbours exon II instead of exon III of variant 1, with no change in the open reading frame. The expression of β-TrCP1-variant 4 is lower than that of variant 1 or 2 in ovarian cancer cell lines, whereas it is abundantly expressed in normal and cancerous ovarian tissues. Moreover, β-TrCP1-variant 2 was aberrantly expressed more than variant 1 in ovarian cancer tissues whereas variant 1 was expressed more in normal tissues. Similar to variants 1 and 2, β-TrCP1-variant 4 directly interacts with β-catenin, one of the substrates of SCF E3 ubiquitin ligase and down-regulates the transcriptional activity and protein expression of β-catenin with a significantly weaker effect than that by variants 1 and 2. However, the co-expression of β-TrCP1-variant 4 with variant 1 in same proportion has no effect, whereas other combinations effectively down-regulate the activity of β-catenin, indicating that the heterodimer of variants 1 and 4 has no function. Thus, β-TrCP1-variant 4 could play a critical role in SCF E3 ligase-mediated ubiquitination by acting as a negative regulator of β-TrCP1-variant 1.