Human Cdc25 A inactivation in response to S phase inhibition and its role in preventing premature mitosis.
The Cdc25 A phosphatase is required for the G1-S transition of the cell cycle and is overexpressed in human cancers. We found that it is ubiquitylated and rapidly degraded by the proteasome and that its levels increase from G1 until mitosis. By treating cells with the DNA synthesis inhibitor hydroxyurea, Cdc25 A rapidly decreased in abundance, and this was accompanied by an increase in Cdk2 phosphotyrosine content and a decrease in Cdk2 kinase activity. Cdc25 A overexpression altered the ability of cells to arrest in the presence of hydroxyurea, and caused them to undergo premature chromosome condensation. Cdc25 A overexpression could render tumor cells less sensitive to DNA replication checkpoints, thereby contributing to their genomic instability.
European Institute of Oncology, Milan, Italy.
M
M
Molinari
C
C
Mercurio
J
J
Dominguez
F
F
Goubin
G F
GF
Draetta
D001973:Bromodeoxyuridine / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D016193:G1 Phase / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D008938:Mitosis / Q000502:physiology; D015739:Nocodazole / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D016196:S Phase / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D014452:Ubiquitins / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000378:metabolism*
D019384:Nucleic Acid Synthesis Inhibitors; D011500:Protein Synthesis Inhibitors; D014452:Ubiquitins; D003513:Cycloheximide; D012264:Ribonucleotide Reductases; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; D001973:Bromodeoxyuridine; D015739:Nocodazole; D006918:Hydroxyurea