New alternative phosphorylation sites on the cyclin dependent kinase 1/cyclin a complex in p53-deficient human cells treated with etoposide: possible association with etoposide-induced apoptosis
| Autor: | Ulrike Jahnke, Karen Higginbottom, Adrian C. Newland, Paul D. Allen, Finbarr E. Cotter |
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| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
Cyclin E Cyclin D Clinical Biochemistry Cyclin A Cyclin B Pharmaceutical Science Apoptosis HL-60 Cells environment and public health chemistry.chemical_compound Cyclin-dependent kinase CDC2 Protein Kinase Animals Humans Phosphorylation Etoposide Pharmacology biology Biochemistry (medical) Cell Cycle Tyrosine phosphorylation Cell Biology G2-M DNA damage checkpoint Antineoplastic Agents Phytogenic Cell biology enzymes and coenzymes (carbohydrates) chemistry Multiprotein Complexes biology.protein Cancer research biological phenomena cell phenomena and immunity Tumor Suppressor Protein p53 K562 Cells Cyclin A2 |
| Zdroj: | Apoptosis : an international journal on programmed cell death. 12(10) |
| ISSN: | 1360-8185 |
| Popis: | Cell cycle arrest is a major cellular response to DNA damage preceding the decision to repair or die. Many malignant cells have non-functional p53 rendering them more “aggressive” in nature. Arrest in p53-negative cells occurs at the G2M cell cycle checkpoint. Failure of DNA damaged cells to arrest at G2 results in entry into mitosis and potential death through aberrant mitosis and/or apoptosis. The pivotal kinase regulating the G2M checkpoint is Cdk1/cyclin B whose activity is controlled by phosphorylation. The p53-negative myeloid leukemia cell lines K562 and HL-60 were used to determine Cdk1 phosphorylation status during etoposide treatment. Cdk1 tyrosine 15 phosphorylation was associated with G2M arrest, but not with cell death. Cdk1 tyrosine 15 phosphorylation also led to suppression of nuclear cyclin B-associated Cdk1 kinase activity. However cell death, associated with broader tyrosine phosphorylation of Cdk1 was not attributed to tyrosine 15 alone. This broader phosphoryl isoform of Cdk1 was associated with cyclin A and not cyclin B. Alternative phosphorylations sites were predicted as tyrosines 4, 99 and 237 by computer analysis. No similar pattern was found on Cdk2. These findings suggest novel Cdk1 phosphorylation sites, which appear to be associated with p53-independent cell death following etoposide treatment. |
| Databáze: | OpenAIRE |
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