Adenomatous polyposis coli protein contains two nuclear export signals andshuttles between the nucleus and cytoplasm

Mutational inactivation of the adenomatous polyposis coil (APC) tumor suppr essor initiates most hereditary and sporadic colon carcinomas. Although APC protein is located in both the cytoplasm and the nucleus, the protein doma ins required to maintain a predominantly cytoplasmic localization are unkno wn. Here, we demonstrate that nuclear export of APC is mediated by two intr insic, leucine-rich, nuclear export signals (NESs) located near the amino t erminus. Each NEs was able to induce the nuclear export of a fused carrier protein. Both APC NESs were independently able to interact with the Crm1 nu clear export factor and substitute for the HIV-1 Rev NEs to mediate nuclear mRNA export. Both APC NESs functioned within the context of APC sequence: an amino-terminal APC peptide containing both NESs interacted with Crm1 and showed nuclear export in a heterokaryon nucleocytoplasmic shuttling assay. Also, mutation of both APC NESs resulted in the nuclear accumulation of th e full-length, similar to 320-kDa APC protein, further establishing that th e two intrinsic APC NESs are necessary for APC protein nuclear export. More over, endogenous APC accumulated in the nucleus of cells treated with the C rm1-specific nuclear export inhibitor leptomycin B, Together, these data in dicate that APC is a nucleocytoplasmic shuttle protein whose predominantly cytoplasmic localization requires NES function and suggests that APC may be important for signaling between the nuclear and cytoplasmic compartments o f epithelial cells.