title: Antagonistic crosstalk between APC and HIF-1α.
abstract: Most colorectal cancers have mutations in the tumor suppressor APC. The best-understood function of APC is its participation in a protein complex that regulates the availability of β-catenin. Solid tumors are characterized by the presence of hypoxia as well as inflammation, which leads to the upregulation of Hypoxia Inducible Factors like HIF-1α. We recently demonstrated a novel antagonistic link between APC and HIF-1α. We found that hypoxia results in reduced levels of APC mRNA and protein via a direct HIF-1α-dependent mechanism. Similarly, APC mediates the repression of HIF-1α. However, this requires wild-type APC, low levels of β-catenin and NFκB activity. These results reveal the downregulation of APC as a novel mechanism that contributes to the survival advantage induced by hypoxia and cytokines such as TNFα. Our data indicate that loss-of-function mutations in APC result in the engagement of the hypoxia response. Importantly, this suggests that other stimuli that induce HIF, such as inflammatory cytokines and oncogenes, alter APC function.
authors.affiliation: University of Dundee, Dundee, Scotland, UK.
authors.forename: Inke
authors.initials: I
authors.lastname: Näthke
authors.forename: Sonia
authors.initials: S
authors.lastname: Rocha
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D015536:Down-Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051153:Wnt Proteins; D051176:beta Catenin