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Up‐regulation of cdc2 protein during paclitaxel‐induced apoptosis
Author(s) -
Chadebech Philippe,
Truchet Isabelle,
Brichese Laetitia,
Valette Annie
Publication year - 2000
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 - 10.1002/1097-0215(20000915)87:6<779::aid-ijc3>3.0.co;2-4
Subject(s) - paclitaxel , cyclin b1 , cyclin dependent kinase 1 , cyclin b , cyclin dependent kinase , mitosis , biology , cell cycle , cancer research , microbiology and biotechnology , chemistry , apoptosis , cyclin , biochemistry , cancer , genetics
Microtubule damages induced by paclitaxel inhibit proteasome‐dependent degradation of cyclin B, resulting in a sustained activation of cyclin B/cdc2 kinase and a cell cycle arrest in mitosis. It has been previously shown that this kinase activity is also required for paclitaxel‐induced apoptosis. We found here that paclitaxel increased cdc2 mRNA and protein levels and led to an accumulation of cdc2 in the active dephosphorylated form in NIH‐OVCAR‐3 cells. The addition of cycloheximide inhibited the paclitaxel‐induced increase in cdc2 protein level, further indicating that paclitaxel stimulates cdc2 synthesis. This increase in cdc2 synthesis is a consequence of paclitaxel‐induced arrest in mitosis. Indeed, dual analysis of DNA and cdc2 protein contents indicated that cdc2 up‐regulation occurred in cells arrested with a G2/M DNA content. Furthermore, no up‐regulation of cdc2 protein was observed when paclitaxel‐treated cells were prevented from entering mitosis by treatment with purvalanol A, a cyclin‐dependent kinase (CDK) inhibitor, or stimulated to exit mitosis with 2‐AP, a non‐specific kinase inhibitor. In addition, when paclitaxel‐induced apoptosis was inhibited by Bcl‐2 over‐expression, cdc2 up‐regulation did not occur, leading to a lower level of activation of the cyclin B/cdc2 complex. Taken together, these results indicated that paclitaxel‐induced cdc2 protein synthesis participates in a positive feedback loop designed to increase the activity of cyclin B/cdc2 kinase and thus may play a role in paclitaxel‐induced apoptosis. Int. J. Cancer 87:779–786, 2000. © 2000 Wiley‐Liss, Inc.