Targeted degradation of beta-catenin by chimeric F-box fusion proteins.
Adenomatous polyposis coli (APC) tumor suppressor protein, together with Axin and glycogen synthase kinase 3beta (GSK-3beta), forms a Wnt-regulated signaling complex that mediates phosphorylation-dependent degradation of cytoplasmic beta-catenin by ubiquitin-dependent proteolysis. Degradation of phosphorylated beta-catenin is initiated by interaction through the WD40-repeat of a F-box protein beta-TrCP, a component of SCF ubiquitin ligase complex. Mutations in APC, Axin, and beta-catenin that prevent down-regulation of cytoplasmic beta-catenin are found in various types of cancers. In the search for efficient treatment and prevention of malignancies associated with increased levels of cytoplasmic beta-catenin, we created chimeric F-box fusion proteins by replacing the WD40-repeat of beta-TrCP with the beta-catenin-binding domains of Tcf4 and E-cadherin. Expression of chimeric F-box fusion proteins successfully promotes degradation of beta-catenin independently of GSK-3beta-mediated phosphorylation. More importantly, this degradation does not require intact APC protein (pAPC).
Liu
Jun
J
Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, CA 94608, USA.
Stevens
Jeffery
J
Matsunami
Nori
N
White
Raymond L
RL
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism
D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D044783:F-Box Proteins; D011993:Recombinant Fusion Proteins; D044786:S-Phase Kinase-Associated Proteins; D015534:Trans-Activators; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins