G1-checkpoint Function Including a Cyclin-dependent Kinase 2 Regulatory Pathway as Potential Determinant of 7-Hydroxystaurosporine (UCN-01)-induced Apoptosis and G1-phase Accumulation

Autor: Kazuyo Sugiyama, Makiko Shimizu, Tatsuya Tamaoki, Tadakazu Akiyama, Shiro Akinaga
Rok vydání: 1999
Předmět:
Cyclin-Dependent Kinase Inhibitor p21
G1 checkpoint
endocrine system
Cancer Research
Cell cycle checkpoint
Antineoplastic Agents
Apoptosis
Cell Cycle Proteins
7–Hydroxystaurosporine (UCN‐01)
Protein Serine-Threonine Kinases
Retinoblastoma Protein
Article
Alkaloids
Cyclin-dependent kinase
Cyclins
CDC2-CDC28 Kinases
Tumor Cells
Cultured
otorhinolaryngologic diseases
Humans
Enzyme Inhibitors
Phosphorylation
Kinase activity
Protein kinase A
Cell Line
Transformed
biology
Cyclin-dependent kinase 4
Kinase
Tumor Suppressor Proteins
Cell Cycle
Cyclin-Dependent Kinase 2
Cyclin-dependent kinase 2
G1 Phase
Cell cycle
Staurosporine
Cyclin-Dependent Kinases
Growth Inhibitors
Oncology
Cancer research
biology.protein
Apoptosis –Cyclin‐dependent kinase 2
biological phenomena
cell phenomena
and immunity
Microtubule-Associated Proteins
Cyclin-Dependent Kinase Inhibitor p27
G1–phase accumulation
Signal Transduction
Zdroj: Japanese Journal of Cancer Research : Gann
ISSN: 0910-5050
DOI: 10.1111/j.1349-7006.1999.tb00721.x
Popis: 7-Hydroxystaurosporine (UCN-01), which was originally identified as a protein kinase C selective inhibitor, is currently in clinical trials as an anti-cancer drug. We previously showed that UCN-01 induced preferential G1-phase accumulation in tumor cells and this effect was associated with the retinoblastoma (Rb) protein and its regulatory factors, such as cyclin-dependent kinase 2 (CDK2) and CDK inhibitors p21 Cip1/WAF1 and p27 Kip1 . We demonstrate here that G1-phase accumulation was induced by UCN-01 in Rb-proficient cell lines (WiDr and HCT116 human colon carcinomas and WI-38 human lung fibroblast), and it was accompanied by dephosphorylation of Rb. In addition, UCN-01-induced G1-phase accumulation was also demonstrated in a Rb-defective cell line (Saos-2 human osteosarcoma), but not in a simian virus 40 (SV40)-transformed cell line (WI-38 VA13). Apoptosis was induced by UCN-01 in the two Rb-deficient cell lines, but not in the other Rb-proficient cell lines. These observations suggest that G1-checkpoint function might be important for cell survival during UCN-01 treatment. In addition, there may be a UCN-01-responsive factor in the G1-checkpoint machinery other than Rb which is targeted by SV40. Further studies revealed a correlation between UCN-01-induced G1-phase accumulation and reduction of cellular CDK2 kinase activity. This reduction was strictly dependent on down-regulation of the Thr 160-phosphorylated form of CDK2 protein, and coincided in part with up-regulation of p27 Kip1 , but it was independent of the level of the p21 Cip1/WAF1 protein. These results suggest that G1-checkpoint function, including a CDK2-regulatory pathway, may be a significant determinant of the sensitivity of tumor cells to UCN-01.
Databáze: OpenAIRE
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