This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Stewart, Z. A.
Right arrow Articles by Pietenpol, J. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stewart, Z. A.
Right arrow Articles by Pietenpol, J. A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, January 1999, p. 205-215, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

p21Waf1/Cip1 Inhibition of Cyclin E/Cdk2 Activity Prevents Endoreduplication after Mitotic Spindle Disruption

Zoe A. Stewart,1,2,3 Steven D. Leach,3,4 and Jennifer A. Pietenpol1,2,3,*

Departments of Biochemistry1 and Surgery,4 Center in Molecular Toxicology,2 and Vanderbilt Cancer Center,3 Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Received 11 March 1998/Returned for modification 13 April 1998/Accepted 30 July 1998

During a normal cell cycle, entry into S phase is dependent on completion of mitosis and subsequent activation of cyclin-dependent kinases (Cdks) in G1. These events are monitored by checkpoint pathways. Recent studies and data presented herein show that after treatment with microtubule inhibitors (MTIs), cells deficient in the Cdk inhibitor p21Waf1/Cip1 enter S phase with a >= 4N DNA content, a process known as endoreduplication, which results in polyploidy. To determine how p21 prevents MTI-induced endoreduplication, the G1/S and G2/M checkpoint pathways were examined in two isogenic cell systems: HCT116 p21+/+ and p21-/- cells and H1299 cells containing an inducible p21 expression vector (HIp21). Both HCT116 p21-/- cells and noninduced HIp21 cells endoreduplicated after MTI treatment. Analysis of G1-phase Cdk activities demonstrated that the induction of p21 inhibited endoreduplication through direct cyclin E/Cdk2 regulation. The kinetics of p21 inhibition of cyclin E/Cdk2 activity and binding to proliferating-cell nuclear antigen in HCT116 p21+/+ cells paralleled the onset of endoreduplication in HCT116 p21-/- cells. In contrast, loss of p21 did not lead to deregulated cyclin D1-dependent kinase activities, nor did p21 directly regulate cyclin B1/Cdc2 activity. Furthermore, we show that MTI-induced endoreduplication in p53-deficient HIp21 cells was due to levels of p21 protein below a threshold required for negative regulation of cyclin E/Cdk2, since ectopic expression of p21 restored cyclin E/Cdk2 regulation and prevented endoreduplication. Based on these findings, we propose that p21 plays an integral role in the checkpoint pathways that restrain normal cells from entering S phase after aberrant mitotic exit due to defects in microtubule dynamics.

* Corresponding author. Mailing address: Vanderbilt University School of Medicine, Department of Biochemistry, 652 Medical Research Building II, 2220 Pierce Ave., Nashville, TN 37232-6305. Phone: (615) 936-1512. Fax: (615) 936-2294 or -1890. E-mail: pietenpol{at}toxicology.mc.vanderbilt.edu.

Molecular and Cellular Biology, January 1999, p. 205-215, Vol. 19, No. 1
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Heilman, S. A., Nordberg, J. J., Liu, Y., Sluder, G., Chen, J. J. (2009). Abrogation of the Postmitotic Checkpoint Contributes to Polyploidization in Human Papillomavirus E7-Expressing Cells. J. Virol. 83: 2756-2764 [Abstract] [Full Text]  
  • Toettcher, J. E., Loewer, A., Ostheimer, G. J., Yaffe, M. B., Tidor, B., Lahav, G. (2009). Distinct mechanisms act in concert to mediate cell cycle arrest. Proc. Natl. Acad. Sci. USA 106: 785-790 [Abstract] [Full Text]  
  • Shen, H., Moran, D. M., Maki, C. G. (2008). Transient Nutlin-3a Treatment Promotes Endoreduplication and the Generation of Therapy-Resistant Tetraploid Cells. Cancer Res. 68: 8260-8268 [Abstract] [Full Text]  
  • Chan, Y. W., On, K. F., Chan, W. M., Wong, W., Siu, H. O., Hau, P. M., Poon, R. Y. C. (2008). The Kinetics of p53 Activation Versus Cyclin E Accumulation Underlies the Relationship between the Spindle-assembly Checkpoint and the Postmitotic Checkpoint. J. Biol. Chem. 283: 15716-15723 [Abstract] [Full Text]  
  • Ivanovska, I., Ball, A. S., Diaz, R. L., Magnus, J. F., Kibukawa, M., Schelter, J. M., Kobayashi, S. V., Lim, L., Burchard, J., Jackson, A. L., Linsley, P. S., Cleary, M. A. (2008). MicroRNAs in the miR-106b Family Regulate p21/CDKN1A and Promote Cell Cycle Progression. Mol. Cell. Biol. 28: 2167-2174 [Abstract] [Full Text]  
  • Matijasevic, Z., Steinman, H. A., Hoover, K., Jones, S. N. (2008). MdmX Promotes Bipolar Mitosis To Suppress Transformation and Tumorigenesis in p53-Deficient Cells and Mice. Mol. Cell. Biol. 28: 1265-1273 [Abstract] [Full Text]  
  • Greene, L. M., Kelly, L., Onnis, V., Campiani, G., Lawler, M., Williams, D. C., Zisterer, D. M. (2007). STI-571 (Imatinib Mesylate) Enhances the Apoptotic Efficacy of Pyrrolo-1,5-Benzoxazepine-6, a Novel Microtubule-Targeting Agent, in Both STI-571-Sensitive and -Resistant Bcr-Abl-Positive Human Chronic Myeloid Leukemia Cells. J. Pharmacol. Exp. Ther. 321: 288-297 [Abstract] [Full Text]  
  • Liu, Y., Heilman, S. A., Illanes, D., Sluder, G., Chen, J. J. (2007). p53-Independent Abrogation of a Postmitotic Checkpoint Contributes to Human Papillomavirus E6-Induced Polyploidy. Cancer Res. 67: 2603-2610 [Abstract] [Full Text]  
  • Gui, Y., Yin, H., He, J.-Y., Yang, S.-H., Walsh, M. P., Zheng, X.-L. (2007). Endoreduplication of human smooth muscle cells induced by 2-methoxyestradiol: a role for cyclin-dependent kinase 2. Am. J. Physiol. Heart Circ. Physiol. 292: H1313-H1320 [Abstract] [Full Text]  
  • Gizatullin, F., Yao, Y., Kung, V., Harding, M. W., Loda, M., Shapiro, G. I. (2006). The Aurora Kinase Inhibitor VX-680 Induces Endoreduplication and Apoptosis Preferentially in Cells with Compromised p53-Dependent Postmitotic Checkpoint Function.. Cancer Res. 66: 7668-7677 [Abstract] [Full Text]  
  • Olaharski, A. J., Sotelo, R., Solorza-Luna, G., Gonsebatt, M. E., Guzman, P., Mohar, A., Eastmond, D. A. (2006). Tetraploidy and chromosomal instability are early events during cervical carcinogenesis. Carcinogenesis 27: 337-343 [Abstract] [Full Text]  
  • Gui, Y., Zheng, X.-L. (2006). 2-Methoxyestradiol Induces Cell Cycle Arrest and Mitotic Cell Apoptosis in Human Vascular Smooth Muscle Cells. Hypertension 47: 271-280 [Abstract] [Full Text]  
  • Si, H., Robertson, E. S. (2006). Kaposi's Sarcoma-Associated Herpesvirus-Encoded Latency-Associated Nuclear Antigen Induces Chromosomal Instability through Inhibition of p53 Function. J. Virol. 80: 697-709 [Abstract] [Full Text]  
  • Dash, B. C., El-Deiry, W. S. (2005). Phosphorylation of p21 in G2/M Promotes Cyclin B-Cdc2 Kinase Activity. Mol. Cell. Biol. 25: 3364-3387 [Abstract] [Full Text]  
  • Chen, J.-G., Yang, C.-P. H., Cammer, M., Band Horwitz, S. (2003). Gene Expression and Mitotic Exit Induced by Microtubule-Stabilizing Drugs. Cancer Res. 63: 7891-7899 [Abstract] [Full Text]  
  • Bahar, R., O-Wang, J., Kawamura, K., Seimiya, M., Wang, Y., Hatano, M., Okada, S., Tokuhisa, T., Watanabe, T., Tagawa, M. (2002). Growth Retardation, Polyploidy, and Multinucleation Induced by Clast3, a Novel Cell Cycle-regulated Protein. J. Biol. Chem. 277: 40012-40019 [Abstract] [Full Text]  
  • Helt, A.-M., Funk, J. O., Galloway, D. A. (2002). Inactivation of both the Retinoblastoma Tumor Suppressor and p21 by the Human Papillomavirus Type 16 E7 Oncoprotein Is Necessary To Inhibit Cell Cycle Arrest in Human Epithelial Cells. J. Virol. 76: 10559-10568 [Abstract] [Full Text]  
  • Borel, F., Lohez, O. D., Lacroix, F. B., Margolis, R. L. (2002). Multiple centrosomes arise from tetraploidy checkpoint failure and mitotic centrosome clusters in p53 and RB pocket protein-compromised cells. Proc. Natl. Acad. Sci. USA 99: 9819-9824 [Abstract] [Full Text]  
  • Bennin, D. A., Don, A. S. A., Brake, T., McKenzie, J. L., Rosenbaum, H., Ortiz, L., DePaoli-Roach, A. A., Horne, M. C. (2002). Cyclin G2 Associates with Protein Phosphatase 2A Catalytic and Regulatory B' Subunits in Active Complexes and Induces Nuclear Aberrations and a G1/S Phase Cell Cycle Arrest. J. Biol. Chem. 277: 27449-27467 [Abstract] [Full Text]  
  • Li, Y., Dowbenko, D., Lasky, L. A. (2002). AKT/PKB Phosphorylation of p21Cip/WAF1 Enhances Protein Stability of p21Cip/WAF1 and Promotes Cell Survival. J. Biol. Chem. 277: 11352-11361 [Abstract] [Full Text]  
  • Chien, W.-M., Noya, F., Benedict-Hamilton, H. M., Broker, T. R., Chow, L. T. (2002). Alternative Fates of Keratinocytes Transduced by Human Papillomavirus Type 18 E7 during Squamous Differentiation. J. Virol. 76: 2964-2972 [Abstract] [Full Text]  
  • Coleman, S. C., Stewart, Z. A., Day, T. A., Netterville, J. L., Burkey, B. B., Pietenpol, J. A. (2002). Analysis of Cell-Cycle Checkpoint Pathways in Head and Neck Cancer Cell Lines: Implications for Therapeutic Strategies. Arch Otolaryngol Head Neck Surg 128: 167-176 [Abstract] [Full Text]  
  • Chattopadhyay, D., Ghosh, M. K., Mal, A., Harter, M. L. (2001). Inactivation of p21 by E1A Leads to the Induction of Apoptosis in DNA-Damaged Cells. J. Virol. 75: 9844-9856 [Abstract] [Full Text]  
  • Rooney, R. J. (2001). Cell Cycle Attenuation by p120E4F Is Accompanied by Increased Mitotic Dysfunction. Cell Growth Differ. 12: 505-516 [Abstract] [Full Text]  
  • Andreassen, P. R., Lacroix, F. B., Lohez, O. D., Margolis, R. L. (2001). 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. 61: 7660-7668 [Abstract] [Full Text]  
  • Szak, S. T., Mays, D., Pietenpol, J. A. (2001). Kinetics of p53 Binding to Promoter Sites In Vivo. Mol. Cell. Biol. 21: 3375-3386 [Abstract] [Full Text]  
  • Andreassen, P. R., Lohez, O. D., Lacroix, F. B., Margolis, R. L. (2001). Tetraploid State Induces p53-dependent Arrest of Nontransformed Mammalian Cells in G1. Mol. Biol. Cell 12: 1315-1328 [Abstract] [Full Text]  
  • Modestou, M., Puig-Antich, V., Korgaonkar, C., Eapen, A., Quelle, D. E. (2001). The Alternative Reading Frame Tumor Suppressor Inhibits Growth through p21-dependent and p21-independent Pathways. Cancer Res. 61: 3145-3150 [Abstract] [Full Text]  
  • Scott, M. T., Morrice, N., Ball, K. L. (2000). Reversible Phosphorylation at the C-terminal Regulatory Domain of p21Waf1/Cip1 Modulates Proliferating Cell Nuclear Antigen Binding. J. Biol. Chem. 275: 11529-11537 [Abstract] [Full Text]  
  • Loeb, K. R., Loeb, L. A. (2000). Significance of multiple mutations in cancer. Carcinogenesis 21: 379-385 [Abstract] [Full Text]  
  • Stewart, Z. A., Mays, D., Pietenpol, J. A. (1999). Defective G1-S Cell Cycle Checkpoint Function Sensitizes Cells to Microtubule Inhibitor-induced Apoptosis. Cancer Res. 59: 3831-3837 [Abstract] [Full Text]  
  • Liou, J. S., Chen, C.-Y., Chen, J. S., Faller, D. V. (2000). Oncogenic Ras Mediates Apoptosis in Response to Protein Kinase C Inhibition through the Generation of Reactive Oxygen Species. J. Biol. Chem. 275: 39001-39011 [Abstract] [Full Text]  
  • Anglana, M., Debatisse, M. (2001). Dual Control of Replication Timing. STOCHASTIC ONSET BUT PROGRAMMED COMPLETION OF MAMMALIAN CHROMOSOME DUPLICATION. J. Biol. Chem. 276: 36639-36646 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»