Abstract
Ubiquitin-mediated proteolysis of cell cycle regulators is a major element of the cell cycle control. The anaphase-promoting complex (APC/C) is a large multisubunit ubiquitin-protein ligase required for the ubiquitination and degradation of G1 and mitotic checkpoint regulators. APC/C-dependent proteolysis regulates cyclin levels in G1, and triggers the separation of sister chromatids at the metaphase-anaphase transition and the destruction of mitotic cyclins at the end of mitosis. Furthermore, it was recently shown that APC/C regulates the degradation of crucial regulators of signal transduction pathways. We report here gene alterations in several components of this complex in human colon cancer cells, including APC6/CDC16 and APC8/CDC23 which are known to be key function elements. The experimental expression of a truncation mutant of APC8/CDC23 subunit (CDC23DeltaTPR) leads to abnormal levels of APC/C targets such as cyclin B1 and disturbs the cell cycle progression of colon epithelial cells through mitosis. Overall, these data support the hypothesis of a deleterious role of these mutations during colorectal carcinogenesis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anaphase-Promoting Complex-Cyclosome
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Antineoplastic Agents / pharmacology
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Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome
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Apc6 Subunit, Anaphase-Promoting Complex-Cyclosome
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Apc8 Subunit, Anaphase-Promoting Complex-Cyclosome
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Breast Neoplasms / genetics
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Carcinoma, Hepatocellular / genetics
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Cell Cycle / genetics
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Cell Cycle Proteins / drug effects
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Cell Cycle Proteins / genetics
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Colonic Neoplasms / drug therapy
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Colonic Neoplasms / genetics*
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Cyclin B / genetics
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Cyclin B / metabolism
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Cyclin B1
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Epithelial Cells / pathology
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Epithelial Cells / physiology
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Female
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Humans
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Ligases / genetics*
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Ligases / metabolism
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Liver Neoplasms / genetics
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Melanoma / genetics
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Mitosis
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Mutation
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Neuroblastoma / genetics
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Nocodazole / pharmacology
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Ovarian Neoplasms / genetics
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Polymerase Chain Reaction / methods
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Protein Subunits
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Tumor Cells, Cultured
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Ubiquitin-Protein Ligase Complexes*
Substances
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Antineoplastic Agents
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Apc3 Subunit, Anaphase-Promoting Complex-Cyclosome
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Apc6 Subunit, Anaphase-Promoting Complex-Cyclosome
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Apc8 Subunit, Anaphase-Promoting Complex-Cyclosome
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CCNB1 protein, human
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CDC16 protein, human
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CDC23 protein, human
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CDC27 protein, human
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Cell Cycle Proteins
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Cyclin B
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Cyclin B1
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Protein Subunits
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Ubiquitin-Protein Ligase Complexes
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Anaphase-Promoting Complex-Cyclosome
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Ligases
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Nocodazole