The F-box protein beta-TrCp1/Fbw1a interacts with p300 to enhance beta-catenin transcriptional activity.
Hyperactivated beta-catenin is a commonly found molecular abnormality in colon cancer, and its nuclear accumulation is thought to promote the expression of genes associated with cellular proliferation and transformation. The p300 transcriptional co-activator binds to beta-catenin and facilitates transcription by recruiting chromatin remodeling complexes and general transcriptional apparatus. We have found that beta-TrCp1/Fbw1a, a member of the Skp1/Cullin/Rbx1/F-box E3 ubiquitin ligase complex, binds directly to p300 and co-localizes with it to beta-catenin target gene promoters. Our data show that Fbw1a, which normally targets beta-catenin for degradation, works together with p300 to enhance the transcriptional activity of beta-catenin, whereas other F-box/WD40 proteins do not. Fbw1a also cooperates with p300 to co-activate transcription by SMAD3, another Fbw1a ubiquitylation target, but not p53 or HIF-1alpha, which are substrates for other ubiquitin ligase complexes. These results suggest that, although Fbw1a is part of a negative feedback loop for controlling beta-catenin levels in normal cells, its overexpression and binding to p300 may contribute to hyperactivated beta-catenin transcriptional activity in colon cancer cells.
Kimbrel
Erin A
EA
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA.
Kung
Andrew L
AL
D000595:Amino Acid Sequence; D015153:Blotting, Western; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism*; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D008969:Molecular Sequence Data; D019151:Peptide Library; D011401:Promoter Regions, Genetic; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D051176:beta Catenin / Q000235:genetics*; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*
C471644:BTRC protein, human; D044783:F-Box Proteins; D019151:Peptide Library; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; D008156:Luciferases; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human