title: KCTD1 suppresses canonical Wnt signaling pathway by enhancing β-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 β-catenin, but molecular regulation mechanisms of β-catenin stability are not completely known. Here, our recent studies have shown that KCTD1 strongly inhibits TCF/LEF reporter activity. Moreover, KCTD1 interacted with β-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 β-catenin and the BTB domain of KCTD1, especially Position Ala-30 and His-33. Immunofluorescence analysis indicated that KCTD1 promotes the cytoplasmic accumulation of β-catenin. Furthermore, protein stability assays revealed that KCTD1 enhances the ubiquitination/degradation of β-catenin in a concentration-dependent manner in HeLa cells. And the degradation of β-catenin mediated by KCTD1 was alleviated by the proteasome inhibitor, MG132. In addition, KCTD1-mediated β-catenin degradation was dependent on casein kinase 1 (CK1)- and glycogen synthase kinase-3β (GSK-3β)-mediated phosphorylation and enhanced by the E3 ubiquitin ligase β-transducin repeat-containing protein (β-TrCP). Moreover, KCTD1 suppressed the expression of endogenous Wnt downstream genes and transcription factor AP-2α. Finally, we found that Wnt pathway member APC and tumor suppressor p53 influence KCTD1-mediated downregulation of β-catenin. These results suggest that KCTD1 functions as a novel inhibitor of Wnt signaling pathway.
authors.affiliation: Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China.
authors.forename: Fangmei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China.
authors.forename: Wenhuan
authors.initials: W
authors.lastname: Huang
authors.affiliation: Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China.
authors.forename: Zhongheng
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China.
authors.forename: Yuzhong
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wei
authors.affiliation: Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China.
authors.forename: Zhenxing
authors.initials: Z
authors.lastname: Wan
authors.affiliation: Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Hu
authors.affiliation: Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China.
authors.forename: Shuanglin
authors.initials: S
authors.lastname: Xiang
authors.affiliation: Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Ding
authors.affiliation: Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Science, Hunan Normal University, Changsha, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000595:Amino Acid Sequence; D047389:Casein Kinase I / Q000378:metabolism; D056970:Co-Repressor Proteins; D015536:Down-Regulation; D017930:Genes, Reporter / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010957:Plasmids / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D056970:Co-Repressor Proteins; C529677:KCTD1 protein, human; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; D047389:Casein Kinase I; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex
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