Nuclear-cytoplasmic shuttling of APC regulates beta-catenin subcellular localization and turnover.
Mutational inactivation of the APC gene is a key early event in the development of familial adenomatous polyposis and colon cancer. APC suppresses tumour progression by promoting degradation of the oncogenic transcriptional activator beta-catenin. APC gene mutations can lead to abnormally high levels of beta-catenin in the nucleus, and the consequent activation of transforming genes. Here, we show that APC is a nuclear-cytoplasmic shuttling protein, and that it can function as a beta-catenin chaperone. APC contains two active nuclear export sequences (NES) at the amino terminus, and mutagenesis of these conserved motifs blocks nuclear export dependent on the CRM1 export receptor. Treatment of cells with the CRM1-specific export inhibitor leptomycin B shifts APC from cytoplasm to nucleus. beta-catenin localization is also regulated by CRM1, but in an APC-dependent manner. Transient expression of wild-type APC in SW480 (APCmut/mut) colon cancer cells enhances nuclear export and degradation of beta-catenin, and these effects can be blocked by mutagenesis of the APC NES. These findings suggest that wild-type APC controls the nuclear accumulation of beta-catenin by a combination of nuclear export and cytoplasmic degradation.
Henderson
B R
BR
Westmead Institute for Cancer Research, University of Sydney, Westmead Millenium Institute, Westmead NSW 2145, Australia. beric_henderson@wmi.usyd.edu.au
D016475:3T3 Cells; D021581:Active Transport, Cell Nucleus; D025601:Adenomatous Polyposis Coli Protein; D000595:Amino Acid Sequence; D000818:Animals; D060466:Axin Protein; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D028884:Karyopherins; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000378:metabolism; D021382:Protein Sorting Signals; D011506:Proteins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D013347:Subcellular Fractions; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D051176:beta Catenin; D000097606:Exportin 1 Protein
D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D028884:Karyopherins; D009687:Nuclear Proteins; D021382:Protein Sorting Signals; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D015534:Trans-Activators; D051176:beta Catenin; D000097606:Exportin 1 Protein; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse