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Research ArticleArticle

The Cyclin-Dependent Kinase Inhibitor Roscovitine Inhibits RNA Synthesis and Triggers Nuclear Accumulation of p53 That Is Unmodified at Ser15 and Lys382

Mats Ljungman and Michelle T. Paulsen
Molecular Pharmacology October 2001, 60 (4) 785-789;
Mats Ljungman
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Michelle T. Paulsen
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Abstract

Roscovitine has been shown to induce the accumulation of the tumor suppressor p53, to arrest cells in the G1 and G2/M phases of the cell cycle, and to induce apoptosis in human cells. Although these cellular effects of roscovitine are thought to be caused directly by its specific inhibition of cyclin-dependent kinases, other mechanisms may contribute as well. In this study, we investigated whether roscovitine interferes with transcription in human cells. We have previously shown that blockage of transcription is a trigger for the induction of p53 and apoptosis in human fibroblasts. Here we show that mRNA synthesis is suppressed significantly by roscovitine in human cells. Furthermore, our results suggest that the mechanism by which roscovitine inhibits RNA synthesis involves the inhibition of the phosphorylation of the carboxyl-terminal domain of RNA polymerase II. Cells treated with roscovitine at doses that affected transcription were found to accumulate p53 in the nucleus; curiously, however, the nuclear accumulation of p53 was not accompanied by modifications at either the Ser15 or Lys382 sites of p53. We conclude that roscovitine is a potent inhibitor of RNA synthesis and that this inhibition may be responsible for the accumulation of nuclear p53.

Footnotes

  • This work was supported by Grant CA82376-01 from the National Institutes of Health.

  • Abbreviations:
    roscovitine
    2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine
    TCA
    trichloroacetic acid
    Cdk
    cyclin-dependent kinase
    PBS
    phosphate-buffered saline
    PBSBT
    phosphate-buffered saline with bovine serum albumin and Tween-20
    CTD
    carboxyl terminal domain
    DRB
    5,6-dichloro-1-β-d-ribofuranosylbenzimidazole
    H7
    1-(5-isoquinolinylsulfonyl)-3-methylpiperazine
    Lys382
    Lys382 acetyl-specific antibody
    • Received February 7, 2001.
    • Accepted June 28, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 60 (4)
Molecular Pharmacology
Vol. 60, Issue 4
1 Oct 2001
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Research ArticleArticle

The Cyclin-Dependent Kinase Inhibitor Roscovitine Inhibits RNA Synthesis and Triggers Nuclear Accumulation of p53 That Is Unmodified at Ser15 and Lys382

Mats Ljungman and Michelle T. Paulsen
Molecular Pharmacology October 1, 2001, 60 (4) 785-789;

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Research ArticleArticle

The Cyclin-Dependent Kinase Inhibitor Roscovitine Inhibits RNA Synthesis and Triggers Nuclear Accumulation of p53 That Is Unmodified at Ser15 and Lys382

Mats Ljungman and Michelle T. Paulsen
Molecular Pharmacology October 1, 2001, 60 (4) 785-789;
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