Nuclear APC.
Mutational inactivation of the tumor suppressor gene APC (Adenomatous polyposis coli) is thought to be an initiating step in the progression of the vast majority ofcolorectal cancers. Attempts to understand APC function have revealed more than a dozen binding partners as well as several subcellular localizations including at cell-cell junctions, associated with microtubules at the leading edge of migrating cells, at the apical membrane, in the cytoplasm and in the nucleus. The present chapter focuses on APC localization and functions in the nucleus. APC contains two classical nuclear localization signals, with a third domain that can enhance nuclear import. Along with two sets of nuclear export signals, the nuclear localization signals enable the large APC protein to shuttle between the nucleus and cytoplasm. Nuclear APC can oppose beta-catenin-mediated transcription. This down-regulation of nuclear beta-catenin activity by APC most likely involves nuclear sequestration of beta-catenin from the transcription complex as well as interaction of APC with transcription corepressor CtBP. Additional nuclear binding partners for APC include transcription factor activator protein AP-2alpha, nuclear export factor Crm1, protein tyrosine phosphatase PTP-BL and perhaps DNA itself. Interaction of APC with polymerase beta and PCNA, suggests a role for APC in DNA repair. The observation that increases in the cytoplasmic distribution of APC correlate with colon cancer progression suggests that disruption of these nuclear functions of APC plays an important role in cancer progression. APC prevalence in the cytoplasm of quiescent cells points to a potential function for nuclear APC in control of cell proliferation. Clear definition of APC's nuclear function(s) will expand the possibilities for early colorectal cancer diagnostics and therapeutics targeted to APC.
Neufeld
Kristi L
KL
Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA. klneuf@ku.edu
D021581:Active Transport, Cell Nucleus; D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D017491:Genes, APC; D006801:Humans; D049790:Nuclear Export Signals; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D051176:beta Catenin / Q000378:metabolism
D025601:Adenomatous Polyposis Coli Protein; D049790:Nuclear Export Signals; D009687:Nuclear Proteins; D051176:beta Catenin