Original Article

Caspase-dependent Cdk Activity Is a Requisite Effector of Apoptotic Death Events

Correspondence to: David S. Ucker, Department of Microbiology and Immunology, University of Illinois College of Medicine, Rm. E803 (M/C 790), 835 South Wolcott, Chicago, IL 60612. Tel:(312) 413-1102 Fax:(312) 996-6415 E-mail:duck{at}uic.edu.

The caspase-dependent activation of cyclin-dependent kinases (Cdks) in varied cell types in response to disparate suicidal stimuli has prompted our examination of the role of Cdks in cell death. We have tested the functional role of Cdk activity in cell death genetically, with the expression of dominant negative Cdk mutants (DN-Cdks) and Cdk inhibitory genes. Here we demonstrate that Cdk2 activity is necessary for death-associated chromatin condensation and other manifestations of apoptotic death, including cell shrinkage and the loss of adhesion to substrate. Susceptibility to the induction of the cell death pathway, including the activation of the caspase cascade, is unimpaired in cells in which Cdk2 activity is inhibited. The direct visualization of active caspase activity in these cells confirms that death-associated Cdk2 acts downstream of the caspase cascade. Cdk inhibition also does not prevent the loss of mitochondrial membrane potential and membrane phospholipid asymmetry, which may be direct consequences of caspase activity, and dissociates these events from apoptotic condensation. Our data suggest that caspase activity is necessary, but not sufficient, for the full physiological cell death program and that a requisite function of the proteolytic caspase cascade is the activation of effector Cdks.

Key Words: physiological cell death, Cdk2, caspase, mitochondria, apoptosis

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Yu, F., Megyesi, J., Price, P. M. (2008). Cytoplasmic initiation of cisplatin cytotoxicity. Am. J. Physiol. Renal Physiol. 295: F44-F52 [Abstract] [Full Text]  
• Lewis, A. E., Rusten, M., Hoivik, E. A., Vikse, E. L., Hansson, M. L., Wallberg, A. E., Bakke, M. (2008). Phosphorylation of Steroidogenic Factor 1 Is Mediated by Cyclin-Dependent Kinase 7. Mol. Endocrinol. 22: 91-104 [Abstract] [Full Text]  
• Zhan, J., Easton, J. B., Huang, S., Mishra, A., Xiao, L., Lacy, E. R., Kriwacki, R. W., Houghton, P. J. (2007). Negative Regulation of ASK1 by p21Cip1 Involves a Small Domain That Includes Serine 98 That Is Phosphorylated by ASK1 In Vivo. Mol. Cell. Biol. 27: 3530-3541 [Abstract] [Full Text]  
• Sohn, D., Essmann, F., Schulze-Osthoff, K., Janicke, R. U. (2006). p21 Blocks Irradiation-Induced Apoptosis Downstream of Mitochondria by Inhibition of Cyclin-Dependent Kinase-Mediated Caspase-9 Activation. Cancer Res. 66: 11254-11262 [Abstract] [Full Text]  
• Price, P. M., Yu, F., Kaldis, P., Aleem, E., Nowak, G., Safirstein, R. L., Megyesi, J. (2006). Dependence of Cisplatin-Induced Cell Death In Vitro and In Vivo on Cyclin-Dependent Kinase 2. J. Am. Soc. Nephrol. 17: 2434-2442 [Abstract] [Full Text]  
• Cvetanovic, M., Mitchell, J. E., Patel, V., Avner, B. S., Su, Y., van der Saag, P. T., Witte, P. L., Fiore, S., Levine, J. S., Ucker, D. S. (2006). Specific Recognition of Apoptotic Cells Reveals a Ubiquitous and Unconventional Innate Immunity. J. Biol. Chem. 281: 20055-20067 [Abstract] [Full Text]  
• Mayya, V., Rezual, K., Wu, L., Fong, M. B., Han, D. K. (2006). Absolute Quantification of Multisite Phosphorylation by Selective Reaction Monitoring Mass Spectrometry: Determination of Inhibitory Phosphorylation Status of Cyclin-Dependent Kinases. Mol. Cell. Proteomics 5: 1146-1157 [Abstract] [Full Text]  
• Bozko, P., Sabisz, M., Larsen, A. K., Skladanowski, A. (2005). Cross-talk between DNA damage and cell survival checkpoints during G2 and mitosis: pharmacologic implications. Molecular Cancer Therapeutics 4: 2016-2025 [Abstract] [Full Text]  
• Wang, J., Devgan, V., Corrado, M., Prabhu, N. S., El-Deiry, W. S., Riccardi, C., Pandolfi, P. P., Missero, C., Dotto, G. P. (2005). Glucocorticoid-induced Tumor Necrosis Factor Receptor Is a p21Cip1/WAF1 Transcriptional Target Conferring Resistance of Keratinocytes to UV Light-induced Apoptosis. J. Biol. Chem. 280: 37725-37731 [Abstract] [Full Text]  
• Jones, A. L., Poon, I. K. H., Hulett, M. D., Parish, C. R. (2005). Histidine-rich Glycoprotein Specifically Binds to Necrotic Cells via Its Amino-terminal Domain and Facilitates Necrotic Cell Phagocytosis. J. Biol. Chem. 280: 35733-35741 [Abstract] [Full Text]  
• Fazal, F., Gu, L., Ihnatovych, I., Han, Y., Hu, W., Antic, N., Carreira, F., Blomquist, J. F., Hope, T. J., Ucker, D. S., de Lanerolle, P. (2005). Inhibiting Myosin Light Chain Kinase Induces Apoptosis In Vitro and In Vivo. Mol. Cell. Biol. 25: 6259-6266 [Abstract] [Full Text]  
• Takahashi, T., Yamasaki, F., Sudo, T., Itamochi, H., Adachi, S., Tamamori-Adachi, M., Ueno, N. T. (2005). Cyclin A-associated kinase activity is needed for paclitaxel sensitivity. Molecular Cancer Therapeutics 4: 1039-1046 [Abstract] [Full Text]  
• Geller, J. I., Szekely-Szucs, K., Petak, I., Doyle, B., Houghton, J. A. (2004). P21Cip1 Is a Critical Mediator of the Cytotoxic Action of Thymidylate Synthase Inhibitors in Colorectal Carcinoma Cells. Cancer Res. 64: 6296-6303 [Abstract] [Full Text]  
• Gartel, A. L., Tyner, A. L. (2002). The Role of the Cyclin-dependent Kinase Inhibitor p21 in Apoptosis. Molecular Cancer Therapeutics 1: 639-649 [Abstract] [Full Text]  
• Sandal, T., Stapnes, C., Kleivdal, H., Hedin, L., Doskeland, S. O. (2002). A Novel, Extraneuronal Role for Cyclin-dependent Protein Kinase 5 (CDK5). MODULATION OF cAMP-INDUCED APOPTOSIS IN RAT LEUKEMIA CELLS. J. Biol. Chem. 277: 20783-20793 [Abstract] [Full Text]  
• Weber, T., Lu, M., Andera, L., Lahm, H., Gellert, N., Fariss, M. W., Korinek, V., Sattler, W., Ucker, D. S., Terman, A., Schroder, A., Erl, W., Brunk, U. T., Coffey, R. J., Weber, C., Neuzil, J. (2002). Vitamin E Succinate Is a Potent Novel Antineoplastic Agent with High Selectivity and Cooperativity with Tumor Necrosis Factor-related Apoptosis-inducing Ligand (Apo2 Ligand) in Vivo. Clin. Cancer Res. 8: 863-869 [Abstract] [Full Text]  
• Ye, K., Zhou, J., Landen, J. W., Bradbury, E. M., Joshi, H. C. (2001). Sustained Activation of p34cdc2 Is Required for Noscapine-induced Apoptosis. J. Biol. Chem. 276: 46697-46700 [Abstract] [Full Text]  
• Zou, X., Tsutsui, T., Ray, D., Blomquist, J. F., Ichijo, H., Ucker, D. S., Kiyokawa, H. (2001). The Cell Cycle-Regulatory CDC25A Phosphatase Inhibits Apoptosis Signal-Regulating Kinase 1. Mol. Cell. Biol. 21: 4818-4828 [Abstract] [Full Text]  
• Cocco, R. E., Ucker, D. S. (2001). Distinct Modes of Macrophage Recognition for Apoptotic and Necrotic Cells Are Not Specified Exclusively by Phosphatidylserine Exposure. Mol. Biol. Cell 12: 919-930 [Abstract] [Full Text]  
• Chang, H. Y., Yang, X. (2000). Proteases for Cell Suicide: Functions and Regulation of Caspases. Microbiol. Mol. Biol. Rev. 64: 821-846 [Abstract] [Full Text]  
• FLORYK, D., UCKER, D. S. (2000). Molecular Mapping of the Physiological Cell Death Process: Mitochondrial Events May Be Disordered. Ann. N. Y. Acad. Sci. 926: 142-148 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents