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CIS ‐diamminedichloroplatinum(II) inhibits p34 cdc2 protein kinase in human lung‐cancer cells
Author(s) -
Nishio Kazuto,
Fujiwara Yasuhiro,
Miyahara Yuki,
Takeda Yuichiro,
Ohira Tatsuo,
Kubota Naohiro,
Ohta Sei,
Funayama Yasunori,
Ogasawara Hayato,
Saijo Nagahiro,
Ohata Masahiro
Publication year - 1993
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910550417
Subject(s) - cyclin dependent kinase 2 , cyclin dependent kinase 1 , protein kinase a , cyclin dependent kinase 4 , biology , dephosphorylation , cell cycle , cyclin dependent kinase 3 , cyclin dependent kinase complex , microbiology and biotechnology , kinase , biochemistry , phosphorylation , cell , phosphatase
cis ‐Diamminedichloroplatinum(II) (CDDP) induced G 2 ‐phase arrest in PC‐9 human cancer cells. To elucidate how CDDP acts on cell‐cycle regulation, we analyzed the effect of CDDP on cell‐cycle regulators such as p34 cdc2 protein kinase. p34 cdc2 protein kinase activity was maximum in G 2 phase and decreased after G 2 /M transition in synchronized PC‐9 human lung cancer cells. Evidence for a phosphorylated p34 cdc2 protein kinase complexed with cyclin B was obtained from cells in G 2 phase and the p34 cdc2 protein kinase appeared to be dephosphorylated at M phase. After exposure to CDDP in G, phase, PC‐9 cells were arrested in G 2 phase. The activation of p34 cdc2 protein kinase was inhibited by CDDP. Cyclin A and wee‐1 kinase were not affected by the exposure to CDDP. Cyclin B was degraded in M phase in PC‐9 cells. Exposure to CDDP did not affect the degradation of cyclin B. Our data suggest that the effect of CDDP on cell‐cycle phase might be regulated by the dephosphorylation of p34 cdc2 protein kinase. To determine whether the p34cdc2 protein kinase is a primary target for CDDP, we examined the direct effect of CDDP on tyrosine dephosphorylation of p34 cdc2 protein kinase in cellular extracts. Cell lysates from synchronized PC‐9 in G 2 phase were immunoprecipitated with p 13‐Sepharose beads. In vitro dephosphorylation of phosphotyrosine of p34 cdc2 protein kinase was observed after exposure to okadaic acid in a concentration‐dependent manner. The dephosphorylation of p34 cdc2 protein kinase by okadaic acid was inhibited by CDDP. We hypothesize that inhibition of p34 cdc2 dephorphorylation by CDDP is important for its growth‐inhibiting properties.