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Cellular effects of olomoucine, an inhibitor of cyclin‐dependent kinases

 

作者: RT Abraham,   M. Acquarone,   A. Andersen,   A. Asensi,   R. Bellé,   F. Berger,   C. Bergounioux,   G. Brunn,   C. Buquet‐Fagot,   D. Fagot,   N. Glab,   H. Goudeau,   M. Goudeau,   P. Guerrier,   P. Houghton,   H. Hendriks,   B. Kloareg,   M. Lippai,   D. Marie,   B. Maro,   L. Meijer,   J. Mester,   O. Mulner‐Lorillon,   SA Poulet,   E. Schierenberg,   B. Schutte,   D. Vaulot,   MH Verlhac,  

 

期刊: Biology of the Cell  (WILEY Available online 1995)
卷期: Volume 83, issue 2‐3  

页码: 105-120

 

ISSN:0248-4900

 

年代: 1995

 

DOI:10.1016/0248-4900(96)81298-6

 

出版商: Blackwell Publishing Ltd

 

关键词: cell cycle;proliferation;protein kinases;cyclin‐dependent kinases;cdc2;cdk1;cdk2;olomoucine;purines;2‐(2‐hydroxyethylamino)‐6‐benzylamino‐9‐methylpurine

 

数据来源: WILEY

 

摘要:

Summary—Olomoucine (2‐(2‐hydroxyethylamino)‐6‐benzylamino‐9‐methylpurine) has been recently described as a competitive inhibitor (ATP‐binding site) of the cell cycle regulating p34cdc2/cyclin B, p33cdk2/cyclin A and p33cdk2/cyclin E kinases, the brain p33cdk5p35 kinase and the ERK1AP‐kinase. The unusual specificity of this compound towards cell cycle regulating enzymes suggests that it could inhibit certain steps of the cell cycle. The cellular effects of olomoucine were investigated in a large variety of plant and animal models. This compound inhibits the G1S transition of unicellular algae (dinoflagellate and diatom). It blocksFucuszygote cleavage and development ofLaminariagametophytes. StimulatedPetuniamesophyl protoplasts are arrested in G1 by olomoucine. By arresting cleavage it blocks the development ofCalanuscopepod larvae. It reversibly inhibits the early cleavages of Caenorhabditiselegansembryos and those of ascidian embryos. Olomoucine inhibits the serotonin‐induced prophase/metaphase transition of clam oocytes; furthermore, it triggers the release of these oocytes from their meiotic metaphase I arrest, and induces nuclei reformation. Olomoucine slows down the prophase/metaphase transition in cleaving sea urchin embryos, but does not affect the duration of the metaphase/anaphase and anaphase/telophase transitions. It also inhibits the prophase/metaphase transition of starfish oocytes triggered by various agonists.Xenopusoocyte maturation, thein vivoandin vitrophosphorylation of elongation factor EF‐1 are inhibited by olomoucine. Mouse oocyte maturation is delayed by this compound, whereas parthenogenetic release from metaphase II arrest is facilitated. Growth of a variety of human cell lines (rhabdomyosarcoma cell lines Rh1, Rh18, Rh28 and Rh30; MCF‐7, KB‐3‐1 and their adriamycin‐resistant counterparts; National Cancer Institute 60 human tumor cell lines comprising nine tumor types) is inhibited by olomoucine. Cell cycle parameter analysis of the non‐small cell lung cancer cell line MR65 shows that olomoucine affects G1 and S phase transits. Olomoucine inhibits DNA synthesis in interleukin‐2‐stimulated T lymphocytes (CTLL‐2 cells) and triggers a G1 arrest similar to interleukin‐2 deprivation. Both cdc2 and cdk2 kinases (immunoprecipitated from nocodazole‐ and hydroxyurea‐treated CTLL‐2 cells, respectively) are inhibited by olomoucine. Both yeast andDrosophilaembryos were insensitive to olomoucine. Taken together the results of this Noah's Ark approach show that olomoucine arrests cells both at the G1S and the G2M boundaries, consistent with the hypothesis of a prevalent effe

 

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