Dataset Information


KCTD1 suppresses canonical Wnt signaling pathway by enhancing ?-catenin degradation.

ABSTRACT: The canonical Wnt signaling pathway controls normal embryonic development, cellular proliferation and growth, and its aberrant activity results in human carcinogenesis. The core component in regulation of this pathway is ?-catenin, but molecular regulation mechanisms of ?-catenin stability are not completely known. Here, our recent studies have shown that KCTD1 strongly inhibits TCF/LEF reporter activity. Moreover, KCTD1 interacted with ?-catenin both in vivo by co-immunoprecipitation as well as in vitro through GST pull-down assays. We further mapped the interaction regions to the 1-9 armadillo repeats of ?-catenin and the BTB domain of KCTD1, especially Position Ala-30 and His-33. Immunofluorescence analysis indicated that KCTD1 promotes the cytoplasmic accumulation of ?-catenin. Furthermore, protein stability assays revealed that KCTD1 enhances the ubiquitination/degradation of ?-catenin in a concentration-dependent manner in HeLa cells. And the degradation of ?-catenin mediated by KCTD1 was alleviated by the proteasome inhibitor, MG132. In addition, KCTD1-mediated ?-catenin degradation was dependent on casein kinase 1 (CK1)- and glycogen synthase kinase-3? (GSK-3?)-mediated phosphorylation and enhanced by the E3 ubiquitin ligase ?-transducin repeat-containing protein (?-TrCP). Moreover, KCTD1 suppressed the expression of endogenous Wnt downstream genes and transcription factor AP-2?. Finally, we found that Wnt pathway member APC and tumor suppressor p53 influence KCTD1-mediated downregulation of ?-catenin. These results suggest that KCTD1 functions as a novel inhibitor of Wnt signaling pathway.

PROVIDER: S-EPMC3988066 | BioStudies |

REPOSITORIES: biostudies

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