Open AccessG1–checkpoint Function Including a Cyclin‐dependent Kinase 2 Regulatory Pathway as Potential Determinant of 7–Hydroxystaurosporine (UCN‐01)‐induced Apoptosis and G1–phase Accumulation
Author(s) -
Akiyama Tadakazu,
Sugiyama Kazuyo,
Shimizu Makiko,
Tamaoki Tatsuya,
Akinaga Shiro
Publication year - 1999
Publication title -
japanese journal of cancer research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 0910-5050
DOI - 10.1111/j.1349-7006.1999.tb00721.x
Subject(s) - cyclin dependent kinase 2 , cyclin dependent kinase , cell cycle , retinoblastoma protein , biology , cancer research , kinase , microbiology and biotechnology , cyclin dependent kinase 4 , cell culture , cyclin dependent kinase 6 , apoptosis , chemistry , protein kinase a , biochemistry , genetics
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 kipl . 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 Thr160–phosphor‐ylated 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.