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

Abstract

beta-transducin repeats-containing protein-1 (beta-TrCP1) serves as the substrate recognition subunit for SCF beta-TrCP E3 ubiquitin ligases, which specifically ubiquitinate phosphorylated substrates. Three variants of beta-TrCP1 are known and act as homodimer or heterodimer complexes. Here, we identified a novel full-sequenced variant, beta-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 beta-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, beta-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, beta-TrCP1-variant 4 directly interacts with beta-catenin, one of the substrates of SCF beta-TrCP E3 ubiquitin ligase and downregulates the transcriptional activity and protein expression of beta-catenin with a significantly weaker effect than that by variants 1 and 2. However, the co-expression of beta-TrCP1-variant 4 with variant 1 in same proportion has no effect, whereas other combinations effectively down-regulate the activity of beta-catenin, indicating that the heterodimer of variants 1 and 4 has no function. Thus, beta-TrCP1-variant 4 could play a critical role in SCF beta-TrCP E3 ligase-mediated ubiquitination by acting as a negative regulator of beta-TrCP1-variant 1. (C) 2021 Elsevier Inc. All rights reserved.