Nuclear accumulation of full-length and truncated adenomatous polyposis coli protein in tumor cells depends on proliferation.
The adenomatous polyposis coli (APC) tumor suppressor is a nucleocytoplasmic protein. The nuclear accumulation of APC was recently found to vary depending on cell density, suggesting that putative APC function(s) in the nucleus is controlled by the establishment of cell contacts. We report here that the density-dependent redistribution of APC between nucleus and cytoplasm prevails in 6/6 thyroid and colorectal carcinoma cell lines. Moreover, mutated APC lacking known nuclear localization sequences had the similar distribution pattern as the full-length protein. APC invariably accumulated in the nuclei of Ki-67 expressing cells, but was largely cytoplasmic when cell cycle exit was induced by serum starvation or at high cell density. APC colocalized with beta-catenin in the nucleus only in one cell line (SW480). Also, APC maintained a predominantly nuclear position in early confluent states when cytoplasmic beta-catenin was recruited to newly formed adherens-like junctions. The results indicate that nuclear targeting of APC is driven by cell cycle entry rather than altered cell-cell contact. The ability of C-terminally truncated APC to accumulate in the nucleus suggests that nuclear import signals other than NLS1(APC) and NLS2(APC) are functionally important. Residual function(s) of N-terminal APC fragments in tumor cells carrying APC mutations might be beneficial to tumor growth and survival.
Fagman
Henrik
H
Institute of Anatomy and Cell Biology, Göteborg University, Box 420, SE-40530 Göteborg, Sweden. henrik.fagman@anatcell.gu.se
Larsson
Fredrik
F
Arvidsson
Yvonne
Y
Meuller
Johan
J
Nordling
Margareta
M
Martinsson
Tommy
T
Helmbrecht
Karen
K
Brabant
Georg
G
Nilsson
Mikael
M
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D009154:Mutation; D019913:Nuclear Localization Signals; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D019394:Ki-67 Antigen; D019913:Nuclear Localization Signals; D015534:Trans-Activators; D051176:beta Catenin