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 Jiang, H.
Right arrow Articles by Zhu, L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jiang, H.
Right arrow Articles by Zhu, L.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, September 1998, p. 5284-5290, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Requirement of Cyclin E-Cdk2 Inhibition in p16INK4a-Mediated Growth Suppression

Hong Jiang,1 Hubert S. Chou,2 and Liang Zhu1,*

Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461,1 and Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 021292

Received 18 December 1997/Returned for modification 10 February 1998/Accepted 17 June 1998

Loss-of-function mutations of p16INK4a have been identified in a large number of human tumors. An established biochemical function of p16 is its ability to specifically inhibit cyclin D-dependent kinases in vitro, and this inhibition is believed to be the cause of the p16-mediated G1 cell cycle arrest after reintroduction of p16 into p16-deficient tumor cells. However, a mutant of Cdk4, Cdk4N158, designed to specifically inhibit cyclin D-dependent kinases through dominant negative interference, was unable to arrest the cell cycle of the same cells (S. van den Heuvel and E. Harlow, Science 262:2050-2054, 1993). In this study, we determined functional differences between p16 and Cdk4N158. We show that p16 and Cdk4N158 inhibit the kinase activity of cellular cyclin D1 complexes through different mechanisms. p16 dissociated cyclin D1-Cdk4 complexes with the release of bound p27KIP1, while Cdk4N158 formed complexes with cyclin D1 and p27. In cells induced to overexpress p16, a higher portion of cellular p27 formed complexes with cyclin E-Cdk2, and Cdk2-associated kinase activities were correspondingly inhibited. Cells engineered to express moderately elevated levels of cyclin E became resistant to p16-mediated growth suppression. These results demonstrate that inhibition of cyclin D-dependent kinase activity may not be sufficient to cause G1 arrest in actively proliferating tumor cells. Inhibition of cyclin E-dependent kinases is required in p16-mediated growth suppression.

* Corresponding author. Mailing address: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Room U-519, Bronx, NY 10461. Phone: (718) 430-3320. Fax: (718) 430-8975. E-mail: lizhu{at}aecom.yu.edu.

Molecular and Cellular Biology, September 1998, p. 5284-5290, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Jones, R., Ruas, M., Gregory, F., Moulin, S., Delia, D., Manoukian, S., Rowe, J., Brookes, S., Peters, G. (2007). A CDKN2A Mutation in Familial Melanoma that Abrogates Binding of p16INK4a to CDK4 but not CDK6. Cancer Res. 67: 9134-9141 [Abstract] [Full Text]  
  • Ruas, M., Gregory, F., Jones, R., Poolman, R., Starborg, M., Rowe, J., Brookes, S., Peters, G. (2007). CDK4 and CDK6 Delay Senescence by Kinase-Dependent and p16INK4a-Independent Mechanisms. Mol. Cell. Biol. 27: 4273-4282 [Abstract] [Full Text]  
  • Braden, W. A., Lenihan, J. M., Lan, Z., Luce, K. S., Zagorski, W., Bosco, E., Reed, M. F., Cook, J. G., Knudsen, E. S. (2006). Distinct Action of the Retinoblastoma Pathway on the DNA Replication Machinery Defines Specific Roles for Cyclin-Dependent Kinase Complexes in Prereplication Complex Assembly and S-Phase Progression. Mol. Cell. Biol. 26: 7667-7681 [Abstract] [Full Text]  
  • Shapiro, G. I. (2006). Cyclin-Dependent Kinase Pathways As Targets for Cancer Treatment. JCO 24: 1770-1783 [Abstract] [Full Text]  
  • Han, J., Tsukada, Y.-i., Hara, E., Kitamura, N., Tanaka, T. (2005). Hepatocyte Growth Factor Induces Redistribution of p21CIP1 and p27KIP1 through ERK-dependent p16INK4a Up-regulation, Leading to Cell Cycle Arrest at G1 in HepG2 Hepatoma Cells. J. Biol. Chem. 280: 31548-31556 [Abstract] [Full Text]  
  • Box, A. H., Demetrick, D. J. (2004). Cell cycle kinase inhibitor expression and hypoxia-induced cell cycle arrest in human cancer cell lines. Carcinogenesis 25: 2325-2335 [Abstract] [Full Text]  
  • Benzeno, S., Narla, G., Allina, J., Cheng, G. Z., Reeves, H. L., Banck, M. S., Odin, J. A., Diehl, J. A., Germain, D., Friedman, S. L. (2004). Cyclin-Dependent Kinase Inhibition by the KLF6 Tumor Suppressor Protein through Interaction with Cyclin D1. Cancer Res. 64: 3885-3891 [Abstract] [Full Text]  
  • Wang, X., Deng, H., Basu, I., Zhu, L. (2004). Induction of Androgen Receptor-Dependent Apoptosis in Prostate Cancer Cells by the Retinoblastoma Protein. Cancer Res. 64: 1377-1385 [Abstract] [Full Text]  
  • Cao, M.-Y., Lee, Y., Feng, N.-P., Al-Qawasmeh, R. A., Viau, S., Gu, X.-P., Lau, L., Jin, H., Wang, M., Vassilakos, A., Wright, J. A., Young, A. H. (2004). NC381, a Novel Anticancer Agent, Arrests the Cell Cycle in G0-G1 and Inhibits Lung Tumor Cell Growth in Vitro and in Vivo. J. Pharmacol. Exp. Ther. 308: 538-546 [Abstract] [Full Text]  
  • Vernell, R., Helin, K., Muller, H. (2003). Identification of Target Genes of the p16INK4A-pRB-E2F Pathway. J. Biol. Chem. 278: 46124-46137 [Abstract] [Full Text]  
  • Matsuda, Y., Ichida, T., Genda, T., Yamagiwa, S., Aoyagi, Y., Asakura, H. (2003). Loss of p16 Contributes to p27 Sequestration by Cyclin D1-Cyclin-dependent Kinase 4 Complexes and Poor Prognosis in Hepatocellular Carcinoma. Clin. Cancer Res. 9: 3389-3396 [Abstract] [Full Text]  
  • Gonzalez, T., Seoane, M., Caamano, P., Vinuela, J., Dominguez, F., Zalvide, J. (2003). Inhibition of Cdk4 Activity Enhances Translation of p27kip1 in Quiescent Rb-negative Cells. J. Biol. Chem. 278: 12688-12695 [Abstract] [Full Text]  
  • Wiebusch, L., Asmar, J., Uecker, R., Hagemeier, C. (2003). Human cytomegalovirus immediate-early over protein 2 (IE2)-mediated activation of cyclin E is cell-cycle-independent and forces S-phase entry in IE2-arrested cells. J. Gen. Virol. 84: 51-60 [Abstract] [Full Text]  
  • Lan, Z., Sever-Chroneos, Z., Strobeck, M. W., Park, C.-H., Baskaran, R., Edelmann, W., Leone, G., Knudsen, E. S. (2002). DNA Damage Invokes Mismatch Repair-dependent Cyclin D1 Attenuation and Retinoblastoma Signaling Pathways to Inhibit CDK2. J. Biol. Chem. 277: 8372-8381 [Abstract] [Full Text]  
  • Geng, Y., Yu, Q., Whoriskey, W., Dick, F., Tsai, K. Y., Ford, H. L., Biswas, D. K., Pardee, A. B., Amati, B., Jacks, T., Richardson, A., Dyson, N., Sicinski, P. (2001). Expression of cyclins E1 and E2 during mouse development and in neoplasia. Proc. Natl. Acad. Sci. USA 10.1073/pnas.231487798v1 [Abstract] [Full Text]  
  • Wei, W., Hemmer, R. M., Sedivy, J. M. (2001). Role of p14ARF in Replicative and Induced Senescence of Human Fibroblasts. Mol. Cell. Biol. 21: 6748-6757 [Abstract] [Full Text]  
  • Ezhevsky, S. A., Ho, A., Becker-Hapak, M., Davis, P. K., Dowdy, S. F. (2001). Differential Regulation of Retinoblastoma Tumor Suppressor Protein by G1 Cyclin-Dependent Kinase Complexes In Vivo. Mol. Cell. Biol. 21: 4773-4784 [Abstract] [Full Text]  
  • Yu, J. T., Foster, R. G., Dean, D. C. (2001). Transcriptional Repression by Rb-E2F and Regulation of Anchorage-Independent Survival. Mol. Cell. Biol. 21: 3325-3335 [Abstract] [Full Text]  
  • Hu, B., Mitra, J., van den Heuvel, S., Enders, G. H. (2001). S and G2 Phase Roles for Cdk2 Revealed by Inducible Expression of a Dominant-Negative Mutant in Human Cells. Mol. Cell. Biol. 21: 2755-2766 [Abstract] [Full Text]  
  • Henshall, S. M., Quinn, D. I., Lee, C. S., Head, D. R., Golovsky, D., Brenner, P. C., Delprado, W., Stricker, P. D., Grygiel, J. J., Sutherland, R. L. (2001). Overexpression of the Cell Cycle Inhibitor p16INK4A in High-grade Prostatic Intraepithelial Neoplasia Predicts Early Relapse in Prostate Cancer Patients. Clin. Cancer Res. 7: 544-550 [Abstract] [Full Text]  
  • Foster, J. S., Henley, D. C., Bukovsky, A., Seth, P., Wimalasena, J. (2001). Multifaceted Regulation of Cell Cycle Progression by Estrogen: Regulation of Cdk Inhibitors and Cdc25A Independent of Cyclin D1-Cdk4 Function. Mol. Cell. Biol. 21: 794-810 [Abstract] [Full Text]  
  • Grimison, B., Langan, T. A., Sclafani, R. A. (2000). p16Ink4a Tumor Suppressor Function in Lung Cancer Cells Involves Cyclin-dependent Kinase 2 Inhibition by Cip/Kip Protein Redistribution. Cell Growth Differ. 11: 507-515 [Abstract] [Full Text]  
  • Awad, M. M., Gruppuso, P. A. (2000). Cell Cycle Control during Liver Development in the Rat: Evidence Indicating a Role for Cyclin D1 Posttranscriptional Regulation. Cell Growth Differ. 11: 325-334 [Abstract] [Full Text]  
  • Santoni-Rugiu, E., Falck, J., Mailand, N., Bartek, J., Lukas, J. (2000). Involvement of Myc Activity in a G1/S-Promoting Mechanism Parallel to the pRb/E2F Pathway. Mol. Cell. Biol. 20: 3497-3509 [Abstract] [Full Text]  
  • Swarbrick, A., Lee, C. S. L., Sutherland, R. L., Musgrove, E. A. (2000). Cooperation of p27Kip1 and p18INK4c in Progestin-Mediated Cell Cycle Arrest in T-47D Breast Cancer Cells. Mol. Cell. Biol. 20: 2581-2591 [Abstract] [Full Text]  
  • Zindy, F., van Deursen, J., Grosveld, G., Sherr, C. J., Roussel, M. F. (2000). INK4d-Deficient Mice Are Fertile Despite Testicular Atrophy. Mol. Cell. Biol. 20: 372-378 [Abstract] [Full Text]  
  • Grossel, M. J., Baker, G. L., Hinds, P. W. (1999). cdk6 Can Shorten G1 Phase Dependent upon the N-terminal INK4 Interaction Domain. J. Biol. Chem. 274: 29960-29967 [Abstract] [Full Text]  
  • Wong, D. J., Foster, S. A., Galloway, D. A., Reid, B. J. (1999). Progressive Region-Specific De Novo Methylation of the p16 CpG Island in Primary Human Mammary Epithelial Cell Strains during Escape from M0 Growth Arrest. Mol. Cell. Biol. 19: 5642-5651 [Abstract] [Full Text]  
  • Kohn, K. W. (1999). Molecular Interaction Map of the Mammalian Cell Cycle Control and DNA Repair Systems. Mol. Biol. Cell 10: 2703-2734 [Abstract] [Full Text]  
  • Sherr, C. J., Roberts, J. M. (1999). CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13: 1501-1512 [Full Text]  
  • Mitra, J., Dai, C. Y., Somasundaram, K., El-Deiry, W. S., Satyamoorthy, K., Herlyn, M., Enders, G. H. (1999). Induction of p21WAF1/CIP1 and Inhibition of Cdk2 Mediated by the Tumor Suppressor p16INK4a. Mol. Cell. Biol. 19: 3916-3928 [Abstract] [Full Text]  
  • McConnell, B. B., Gregory, F. J., Stott, F. J., Hara, E., Peters, G. (1999). Induced Expression of p16INK4a Inhibits Both CDK4- and CDK2-Associated Kinase Activity by Reassortment of Cyclin-CDK-Inhibitor Complexes. Mol. Cell. Biol. 19: 1981-1989 [Abstract] [Full Text]  
  • Fry, D. W., Bedford, D. C., Harvey, P. H., Fritsch, A., Keller, P. R., Wu, Z., Dobrusin, E., Leopold, W. R., Fattaey, A., Garrett, M. D. (2001). Cell Cycle and Biochemical Effects of PD 0183812. A POTENT INHIBITOR OF THE CYCLIN D-DEPENDENT KINASES CDK4 AND CDK6. J. Biol. Chem. 276: 16617-16623 [Abstract] [Full Text]  
  • Prall, O. W. J., Carroll, J. S., Sutherland, R. L. (2001). A Low Abundance Pool of Nascent p21WAF1/Cip1 Is Targeted by Estrogen to Activate Cyclin E{middle dot}Cdk2. J. Biol. Chem. 276: 45433-45442 [Abstract] [Full Text]  
  • Geng, Y., Yu, Q., Whoriskey, W., Dick, F., Tsai, K. Y., Ford, H. L., Biswas, D. K., Pardee, A. B., Amati, B., Jacks, T., Richardson, A., Dyson, N., Sicinski, P. (2001). Expression of cyclins E1 and E2 during mouse development and in neoplasia. Proc. Natl. Acad. Sci. USA 98: 13138-13143 [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»