| Description |
Mutation of the Adenomatous Polyposis Coli (APC) gene is an early step in the development of colorectal carcinomas. To provide clues for APC's role in tumor suppression, the subcellular distribution of APC was studied, and APC was found to localize to both the cytoplasm and the nucleus of normal human epithelial cells. The objectives of this study were to characterize the intrinsic signals that mediate APC nuclear import, examine the regulation of APC's nuclear localization and its mechanism, and study the functional importance of this nuclear localization. Two functional nuclear localization signals (NLSs), NLS1[APC] and NLS2[APC], were identified. They were each sufficient to target the cytoplasmic protein beta-galactosidase to the nucleus, and they were both necessary for optimal nuclear import of full-length APC protein. To analyze how cellular context affects APC distribution, several cellular contexts were examined including cell density, cell cycle, cell-cell contact, and extracellular calcium. We determined that cell density, but not cell cycle, influenced APC's subcellular distribution. Further analysis of the two defined NLSs revealed that the adjacent potential CK2 and PKA sites regulated NLS2[APC]-mediated nuclear import. Phosphorylation at the CK2 site increased and phosphorylation at the PKA site decreased NLS2<sub> APC |
