This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lock, R. B. Search for Related Content PubMed PubMed Citation Articles by Lock, R. B.

Inhibition of p34^cdc2 Kinase Activation, p34^cdc2 Tyrosine Dephosphorylation, and Mitotic Progression in Chinese Hamster Ovary Cells Exposed to Etoposide¹

The J. Graham Brown Cancer Center, Departments of Medicine and Biochemistry, University of Louisville, Louisville, Kentucky 40292

p34^cdc2 kinase, an enzyme essential for mitosis in mammalian cells, may play a role in etoposide-induced G₂ phase arrest of Chinese hamster ovary cells. In this study, etoposide is shown to cause inhibition of a specific p34^cdc2 kinase activation pathway, that of tyrosine dephosphorylation. Exposure of asynchronously dividing cells to etoposide caused a simultaneous rapid decline of both mitotic index and p34^cdc2 kinase activity, suggesting that the kinase was not activated and that the arrest point was in late G₂ phase. Using synchronized cells, p34^cdc2 kinase exhibited maximal activity at the G₂/M transition. Activation of the kinase and the onset of mitosis were accompanied by increased electrophoretic mobility and tyrosine dephosphorylation of the p34^cdc2 protein. A 1-h exposure to etoposide during early G₂ phase inhibited p34^cdc2 kinase activation, its shift in electrophoretic mobility, and its tyrosine dephosphorylation, all of which correlated with a delay in mitotic progression. The interaction between the p34^cdc2 and cyclin B proteins appeared unaffected under etoposide exposure conditions which resulted in greater than 70% inhibition of p34^cdc2 kinase activity and almost complete cessation of transition into mitosis. These data suggest that mammalian cells express a DNA damage-responsive mechanism which controls mitotic progression at the level of p34^cdc2 tyrosine dephosphorylation.

¹ This work was supported by USPHS Grant CA53184 from the NIH.

² To whom requests for reprints should be addressed, at The J. Graham Brown Cancer Center, 529 S. Jackson Street, University of Louisville, Louisville, KY 40292.

Received 10/ 2/91. Accepted 1/23/92.

This article has been cited by other articles:

				S. J. Mistry and G. F. Atweh Therapeutic interactions between stathmin inhibition and chemotherapeutic agents in prostate cancer Mol. Cancer Ther., December 1, 2006; 5(12): 3248 - 3257. [Abstract] [Full Text] [PDF]

				A. Chiarini, J. F. Whitfield, U. Armato, and I. Dal Pra Protein Kinase C-beta II Is an Apoptotic Lamin Kinase in Polyomavirus-transformed, Etoposide-treated pyF111 Rat Fibroblasts J. Biol. Chem., May 17, 2002; 277(21): 18827 - 18839. [Abstract] [Full Text] [PDF]

				P. R. Andreassen, F. B. Lacroix, O. D. Lohez, and R. L. Margolis Neither p21WAF1 Nor 14-3-3{sigma} Prevents G2 Progression to Mitotic Catastrophe in Human Colon Carcinoma Cells after DNA Damage, But p21WAF1 Induces Stable G1 Arrest in Resulting Tetraploid Cells Cancer Res., October 1, 2001; 61(20): 7660 - 7668. [Abstract] [Full Text] [PDF]

				A. J. Janss, A. Maity, C.-B. Tang, R. J. Muschel, W. G. McKenna, L. Sutton, and P. C. Phillips Decreased cyclin B1 expression contributes to G2 delay in human brain tumor cells after treatment with camptothecin Neuro-oncol, January 1, 2001; 3(1): 11 - 21. [Abstract] [PDF]

				L. Qiu, A. Burgess, D. P. Fairlie, H. Leonard, P. G. Parsons, and B. G. Gabrielli Histone Deacetylase Inhibitors Trigger a G2 Checkpoint in Normal Cells That Is Defective in Tumor Cells Mol. Biol. Cell, June 1, 2000; 11(6): 2069 - 2083. [Abstract] [Full Text]

				G. D. Kao, W. G. McKenna, and R. J. Muschel p34Cdc2 Kinase Activity Is Excluded from the Nucleus during the Radiation-induced G2 Arrest in HeLa Cells J. Biol. Chem., December 3, 1999; 274(49): 34779 - 34784. [Abstract] [Full Text] [PDF]

				L. Yu, L. Orlandi, P. Wang, M. S. Orr, A. M. Senderowicz, E. A. Sausville, R. Silvestrini, N. Watanabe, H. Piwnica-Worms, and P. M. O'Connor UCN-01 Abrogates G2 Arrest through a Cdc2-dependent Pathway That Is Associated with Inactivation of the Wee1Hu Kinase and Activation of the Cdc25C Phosphatase J. Biol. Chem., December 11, 1998; 273(50): 33455 - 33464. [Abstract] [Full Text] [PDF]

				A. Borgne and L. Meijer Sequential Dephosphorylation of p34cdc2 on Thr-14 and Tyr-15 at the Prophase/Metaphase Transition J. Biol. Chem., November 1, 1996; 271(44): 27847 - 27854. [Abstract] [Full Text] [PDF]

				W Ongkeko, D. Ferguson, A. Harris, and C Norbury Inactivation of Cdc2 increases the level of apoptosis induced by DNA damage J. Cell Sci., January 8, 1995; 108(8): 2897 - 2904. [Abstract] [PDF]

				P. Clarke, C Klebe, A Wittinghofer, and E Karsenti Regulation of Cdc2/cyclin B activation by Ran, a Ras-related GTPase J. Cell Sci., January 3, 1995; 108(3): 1217 - 1225. [Abstract] [PDF]