Posttranslational modifications of the KI-67 protein coincide with two major checkpoints during mitosis.
Ki-67 is a nuclear protein present in all proliferating cells that are in the active part of the cell division, but not in resting cells. This feature is extensively used in tumor diagnostics to estimate the growth fraction of a given cell population. We now demonstrate that the spatial and temporal regulation of the Ki-67 protein during the cell cycle is associated with mitosis-specific phosphorylation. These posttranslational modifications of the Ki-67 protein are accompanied by a characteristic redistribution of the protein from the interior of the nucleus to the periphery of the condensed chromosomes and vice versa. Phosphorylation could be suppressed by activating cell-cycle checkpoints that control the entry into mitosis through the activity of the cyclin B/cdc2 complex. In vitro experiments confirm that the presence of the cdc2 kinase and its regulatory subunit cyclin B is required for the phosphorylation of the Ki-67 protein. We further demonstrated that the Ki-67 protein is a new member of the family of MPM-2 reactive phosphoproteins, which includes both structural and functional proteins that are necessary for the control and timing of mitosis. Phosphorylation and dephosphorylation of the Ki-67 protein are therefore controlled by key regulatory structures of the cell cycle and occur at two hallmark events within the cell cycle: the breakdown and the reorganization of the nucleus during mitosis.
Endl
E
E
Department of Immunology and Cell Biology, Division of Molecular Immunology, Research Center Borstel, Borstel, Germany.
Gerdes
J
J
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000705:Anaphase / Q000502:physiology; D000906:Antibodies; D000970:Antineoplastic Agents / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016195:G2 Phase / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D006367:HeLa Cells; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D008677:Metaphase / Q000502:physiology*; D015739:Nocodazole / Q000494:pharmacology; D010750:Phosphoproteins / Q000276:immunology / Q000378:metabolism; D010761:Phosphorus Radioisotopes; D010766:Phosphorylation; D011418:Prophase / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D013936:Thymidine / Q000037:antagonists & inhibitors
D000906:Antibodies; D000970:Antineoplastic Agents; D019926:Cyclin B; D004791:Enzyme Inhibitors; D000939:Epitopes; D019394:Ki-67 Antigen; D010750:Phosphoproteins; D010761:Phosphorus Radioisotopes; D000255:Adenosine Triphosphate; D016203:CDC2 Protein Kinase; D019311:Staurosporine; D015739:Nocodazole; D013936:Thymidine