Cell Growth & Differentiation, Vol 3, Issue 11 811-817, Copyright © 1992 by American Association of Cancer Research

ARTICLES

Staurosporine overrides checkpoints for mitotic onset in BHK cells

SW Tam and R Schlegel
Department of Molecular and Cellular Toxicology, Harvard School of Public Health, Boston, Massachusetts 02115.

Under normal conditions, mammalian cells will not initiate mitosis in the presence of either unreplicated or damaged DNA. We report here that staurosporine, a tumor promoter and potent protein kinase inhibitor, can uncouple mitosis from the completion of DNA replication and override DNA damage-induced G2 delay. Syrian hamster (BHK) fibroblasts that were arrested in S phase underwent premature mitosis at concentrations as low as 1 ng/ml, with maximum activity seen at 50 ng/ml. Histone H1 kinase activity was increased to approximately one-half the level found in normal mitotic cells. Inhibition of protein synthesis during staurosporine treatment blocked premature mitosis and suppressed the increase in histone H1 kinase activity. In asynchronously growing cells, staurosporine transiently increased the mitotic index and histone H1 kinase activity but did not induce S phase cells to undergo premature mitosis, indicating a requirement for S phase arrest. Staurosporine also bypassed the cell cycle checkpoint that prevents the onset of mitosis in the presence of damaged DNA. The delay in mitotic onset resulting from gamma radiation was reduced when irradiation was followed immediately by exposure to 50 ng/ml of staurosporine. These findings indicate that inhibition of protein phosphorylation by staurosporine can override two important checkpoints for the initiation of mitosis in BHK cells.

This article has been cited by other articles:

				B. L. Schneider and M. Kulesz-Martin Destructive cycles: the role of genomic instability and adaptation in carcinogenesis Carcinogenesis, November 1, 2004; 25(11): 2033 - 2044. [Abstract] [Full Text] [PDF]

				T. Kawabe G2 checkpoint abrogators as anticancer drugs Mol. Cancer Ther., April 1, 2004; 3(4): 513 - 519. [Abstract] [Full Text] [PDF]

				N. T. Rundle, L. Xu, R. J. Andersen, and M. Roberge G2 DNA Damage Checkpoint Inhibition and Antimitotic Activity of 13-Hydroxy-15-oxozoapatlin J. Biol. Chem., December 14, 2001; 276(51): 48231 - 48236. [Abstract] [Full Text] [PDF]

				J. R. Jackson, A. Gilmartin, C. Imburgia, J. D. Winkler, L. A. Marshall, and A. Roshak An Indolocarbazole Inhibitor of Human Checkpoint Kinase (Chk1) Abrogates Cell Cycle Arrest Caused by DNA Damage Cancer Res., February 1, 2000; 60(3): 566 - 572. [Abstract] [Full Text]

				R. Rowley and J. Zhang Caffeine-Mediated Override of Checkpoint Controls: A Requirement for rhp6 (Schizosaccharomyces pombe) Genetics, May 1, 1999; 152(1): 61 - 71. [Abstract] [Full Text]

				S. Wang, C Norbury, A. Harris, and T Toda Caffeine can override the S-M checkpoint in fission yeast J. Cell Sci., January 3, 1999; 112(6): 927 - 937. [Abstract] [PDF]

				D. Curman, B. Cinel, D. E. Williams, N. Rundle, W. D. Block, A. A. Goodarzi, J. R. Hutchins, P. R. Clarke, B.-B. Zhou, S. P. Lees-Miller, et al. Inhibition of the G2 DNA Damage Checkpoint and of Protein Kinases Chk1 and Chk2 by the Marine Sponge Alkaloid Debromohymenialdisine J. Biol. Chem., May 18, 2001; 276(21): 17914 - 17919. [Abstract] [Full Text] [PDF]