This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Leach, S. D. Articles by Pietenpol, J. A. Search for Related Content PubMed PubMed Citation Articles by Leach, S. D. Articles by Pietenpol, J. A.

Negative Regulation of Wee1 Expression and Cdc2 Phosphorylation during p53-mediated Growth Arrest and Apoptosis¹

Departments of Surgery [S. D. L., H. A. G., S. Y. S., L. Y.] and Biochemistry [C. D. S., C. J. K., J. A. P.], The Vanderbilt Cancer Center, Center in Molecular Toxicology, Vanderbilt University Medical Center, and the Surgical Service, Nashville Veterans Affairs Medical Center [S. D. L.], Nashville, Tennessee 37232

The G₂ cell cycle checkpoint protects cells from potentially lethal mitotic entry after DNA damage. This checkpoint involves inhibitory phosphorylation of Cdc2 at the tyrosine-15 (Y15) position, mediated in part by the Wee1 protein kinase. Recent evidence suggests that p53 may accelerate mitotic entry after DNA damage and that the override of the G₂ checkpoint may play a role in the induction of apoptosis by p53. To determine the biochemical mechanism by which p53 inactivates the G₂ checkpoint, the effects of p53 activation on Wee1 expression, Cdc2-Y15 phosphorylation, and cyclin B1-associated Cdc2 kinase activity were examined. Under conditions of either growth arrest or apoptosis, p53 activation resulted in the down-regulation of Wee1 expression and dephosphorylation of Cdc2. A parallel increase in cyclin B1/Cdc2 kinase activity was observed during p53-mediated apoptosis. Negative regulation of the Wee1 expression and Cdc2 phosphorylation by p53 was also evident in thymus tissue from p53^+/+ mice but not from p53^-/- mice. Inactivation of the G₂ checkpoint may contribute to the tumor suppressor activity of p53.

¹ Supported by American Cancer Society Clinical Oncology Career Development Award #96-46 (S. D. L.), American Cancer Society Institutional Pilot Grant #IN-25-35 (S. D. L.), Burroughs Wellcome Fund (J. A. P.), and NIH Grants CA70856 (J. A. P.), ES00267, and CA68485 (Core services).

² To whom requests for reprints should be addressed, at 652 Medical Research Building II, Vanderbilt University Medical Center, Nashville, TN 37232-6838.

Received 5/ 1/98. Accepted 6/15/98.

This article has been cited by other articles:

				V. Mayya, K. Rezual, L. Wu, M. B. Fong, and D. K. Han Absolute Quantification of Multisite Phosphorylation by Selective Reaction Monitoring Mass Spectrometry: Determination of Inhibitory Phosphorylation Status of Cyclin-Dependent Kinases Mol. Cell. Proteomics, June 1, 2006; 5(6): 1146 - 1157. [Abstract] [Full Text] [PDF]

				A.-C. Goulet, M. Chigbrow, P. Frisk, and M. A. Nelson Selenomethionine induces sustained ERK phosphorylation leading to cell-cycle arrest in human colon cancer cells Carcinogenesis, January 1, 2005; 26(1): 109 - 117. [Abstract] [Full Text] [PDF]

				N. V. Gopee, V. J. Johnson, and R. P. Sharma Sodium Selenite-Induced Apoptosis in Murine B-Lymphoma Cells Is Associated with Inhibition of Protein Kinase C-{delta}, Nuclear Factor {kappa}B, and Inhibitor of Apoptosis Protein Toxicol. Sci., April 1, 2004; 78(2): 204 - 214. [Abstract] [Full Text] [PDF]

				A. M. Kamat, T. Karashima, D. W. Davis, L. Lashinger, M. Bar-Eli, R. Millikan, Y. Shen, C. P. N. Dinney, and D. J. McConkey The proteasome inhibitor bortezomib synergizes with gemcitabine to block the growth of human 253JB-V bladder tumors in vivo Mol. Cancer Ther., March 1, 2004; 3(3): 279 - 290. [Abstract] [Full Text]

				M. Shimada, T. Nakadai, and T.-a. Tamura TATA-Binding Protein-Like Protein (TLP/TRF2/TLF) Negatively Regulates Cell Cycle Progression and Is Required for the Stress-Mediated G2 Checkpoint Mol. Cell. Biol., June 15, 2003; 23(12): 4107 - 4120. [Abstract] [Full Text] [PDF]

				H. Yuan, Y.-M. Xie, and I. S. Y. Chen Depletion of Wee-1 Kinase Is Necessary for both Human Immunodeficiency Virus Type 1 Vpr- and Gamma Irradiation-Induced Apoptosis J. Virol., February 1, 2003; 77(3): 2063 - 2070. [Abstract] [Full Text] [PDF]

				E.-J. Kim, J.-S. Park, and S.-J. Um Identification and Characterization of HIPK2 Interacting with p73 and Modulating Functions of the p53 Family in Vivo J. Biol. Chem., August 23, 2002; 277(35): 32020 - 32028. [Abstract] [Full Text] [PDF]

				D. M. Price, Z. Jin, S. Rabinovitch, and S. D. Campbell Ectopic Expression of the Drosophila Cdk1 Inhibitory Kinases, Wee1 and Myt1, Interferes With the Second Mitotic Wave and Disrupts Pattern Formation During Eye Development Genetics, June 1, 2002; 161(2): 721 - 731. [Abstract] [Full Text] [PDF]

				Y. Wang, J. Li, R. N. Booher, A. Kraker, T. Lawrence, W. R. Leopold, and Y. Sun Radiosensitization of p53 Mutant Cells by PD0166285, a Novel G2 Checkpoint Abrogator Cancer Res., November 1, 2001; 61(22): 8211 - 8217. [Abstract] [Full Text] [PDF]

				D. G. Menter, A. L. Sabichi, and S. M. Lippman Selenium Effects on Prostate Cell Growth Cancer Epidemiol. Biomarkers Prev., November 1, 2000; 9(11): 1171 - 1182. [Abstract] [Full Text]

				C. R. Scoggins, I. M. Meszoely, M. Wada, A. L. Means, L. Yang, and S. D. Leach p53-Dependent acinar cell apoptosis triggers epithelial proliferation in duct-ligated murine pancreas Am J Physiol Gastrointest Liver Physiol, October 1, 2000; 279(4): G827 - G836. [Abstract] [Full Text] [PDF]

				K. Mortensen, J. Skouv, D. M. Hougaard, and L.-I. Larsson Endogenous Endothelial Cell Nitric-oxide Synthase Modulates Apoptosis in Cultured Breast Cancer Cells and Is Transcriptionally Regulated by p53 J. Biol. Chem., December 31, 1999; 274(53): 37679 - 37684. [Abstract] [Full Text] [PDF]

				J.-S. Park, S. Carter, D. B. Reardon, R. Schmidt-Ullrich, P. Dent, and P. B. Fisher Roles for Basal and Stimulated p21Cip-1/WAF1/MDA6 Expression and Mitogen-activated Protein Kinase Signaling in Radiation-induced Cell Cycle Checkpoint Control in Carcinoma Cells Mol. Biol. Cell, December 1, 1999; 10(12): 4231 - 4246. [Abstract] [Full Text]

				W. R. Taylor, S. E. DePrimo, A. Agarwal, M. L. Agarwal, A. H. Schönthal, K. S. Katula, and G. R. Stark Mechanisms of G2 Arrest in Response to Overexpression of p53 Mol. Biol. Cell, November 1, 1999; 10(11): 3607 - 3622. [Abstract] [Full Text]

				M. Murphy, J. Ahn, K. K. Walker, W. H. Hoffman, R. M. Evans, A. J. Levine, and D. L. George Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a Genes & Dev., October 1, 1999; 13(19): 2490 - 2501. [Abstract] [Full Text]

				Z. A. Stewart, D. Mays, and J. A. Pietenpol Defective G1-S Cell Cycle Checkpoint Function Sensitizes Cells to Microtubule Inhibitor-induced Apoptosis Cancer Res., August 1, 1999; 59(15): 3831 - 3837. [Abstract] [Full Text] [PDF]

				C. D. Scatena, Z. A. Stewart, D. Mays, L. J. Tang, C. J. Keefer, S. D. Leach, and J. A. Pietenpol Mitotic Phosphorylation of Bcl-2 during Normal Cell Cycle Progression and Taxol-induced Growth Arrest J. Biol. Chem., November 13, 1998; 273(46): 30777 - 30784. [Abstract] [Full Text] [PDF]