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JW Harper, SJ Elledge, K Keyomarsi, B Dynlacht, LH Tsai, P Zhang, S Dobrowolski, C Bai, L Connell-Crowley and E Swindell
Verna & Marrs McLean Department of Biochemistry, Baylor College of Medicine, Houston, Texas 77030, USA.
p21Cip1 is a cyclin-dependent kinase (Cdk) inhibitor that is transcriptionally activated by p53 in response to DNA damage. We have explored the interaction of p21 with the currently known Cdks. p21 effectively inhibits Cdk2, Cdk3, Cdk4, and Cdk6 kinases (Ki 0.5-15 nM) but is much less effective toward Cdc2/cyclin B (Ki approximately 400 nM) and Cdk5/p35 (Ki > 2 microM), and does not associate with Cdk7/cyclin H. Overexpression of P21 arrests cells in G1. Thus, p21 is not a universal inhibitor of Cdks but displays selectivity for G1/S Cdk/cyclin complexes. Association of p21 with Cdks is greatly enhanced by cyclin binding. This property is shared by the structurally related inhibitor p27, suggesting a common biochemical mechanism for inhibition. With respect to Cdk2 and Cdk4 complexes, p27 shares the inhibitory potency of p21 but has slightly different kinase specificities. In normal diploid fibroblasts, the vast majority of active Cdk2 is associated with p21, but this active kinase can be fully inhibited by addition of exogenous p21. Reconstruction experiments using purified components indicate that multiple molecules of p21 can associate with Cdk/cyclin complexes and inactive complexes contain more than one molecule of p21. Together, these data suggest a model whereby p21 functions as an inhibitory buffer whose levels determine the threshold kinase activity required for cell cycle progression.
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 R. Soni, T. O'Reilly, P. Furet, L. Muller, C. Stephan, S. Zumstein-Mecker, H. Fretz, D. Fabbro, and B. Chaudhuri Selective In Vivo and In Vitro Effects of a Small Molecule Inhibitor of Cyclin-Dependent Kinase 4 J Natl Cancer Inst, March 21, 2001; 93(6): 436 - 446. [Abstract] [Full Text] [PDF]
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 J. S. Richards Graafian Follicle Function and Luteinization in Nonprimates Reproductive Sciences, January 1, 2001; 8(1_suppl): S21 - S23. [Abstract] [PDF]
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X. Chen, M. Lowe, T. Herliczek, M. J. Hall, C. Danes, D. A. Lawrence, and K. Keyomarsi Protection of Normal Proliferating Cells Against Chemotherapy by Staurosporine-Mediated, Selective, and Reversible G1 Arrest J Natl Cancer Inst, December 20, 2000; 92(24): 1999 - 2008. [Abstract] [Full Text] [PDF]
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 R. T. Ballock, X. Zhou, L. M. Mink, D. H. C. Chen, B. C. Mita, and M. C. Stewart Expression of Cyclin-Dependent Kinase Inhibitors in Epiphyseal Chondrocytes Induced to Terminally Differentiate with Thyroid Hormone Endocrinology, December 1, 2000; 141(12): 4552 - 4557. [Abstract] [Full Text] [PDF]
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H. Miyata, Y. Doki, H. Shiozaki, M. Inoue, M. Yano, Y. Fujiwara, H. Yamamoto, K. Nishioka, K. Kishi, and M. Monden CDC25B and p53 Are Independently Implicated in Radiation Sensitivity for Human Esophageal Cancers Clin. Cancer Res., December 1, 2000; 6(12): 4859 - 4865. [Abstract] [Full Text]
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 I. Matushansky, F. Radparvar, and A. I. Skoultchi Manipulating the onset of cell cycle withdrawal in differentiated erythroid cells with cyclin-dependent kinases and inhibitors Blood, October 15, 2000; 96(8): 2755 - 2764. [Abstract] [Full Text] [PDF]
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 O. Genbacev, M. T. McMaster, and S. J. Fisher A Repertoire of Cell Cycle Regulators Whose Expression Is Coordinated with Human Cytotrophoblast Differentiation Am. J. Pathol., October 1, 2000; 157(4): 1337 - 1351. [Abstract] [Full Text] [PDF]
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C. de la Fuente, F. Santiago, S. Y. Chong, L. Deng, T. Mayhood, P. Fu, D. Stein, T. Denny, F. Coffman, N. Azimi, et al. Overexpression of p21waf1 in Human T-Cell Lymphotropic Virus Type 1-Infected Cells and Its Association with Cyclin A/cdk2 J. Virol., August 15, 2000; 74(16): 7270 - 7283. [Abstract] [Full Text]
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P. Castella, S. Sawai, K. Nakao, J. A. Wagner, and M. Caudy HES-1 Repression of Differentiation and Proliferation in PC12 Cells: Role for the Helix 3-Helix 4 Domain in Transcription Repression Mol. Cell. Biol., August 15, 2000; 20(16): 6170 - 6183. [Abstract] [Full Text]
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M. A. Cotter II and E. S. Robertson Modulation of Histone Acetyltransferase Activity through Interaction of Epstein-Barr Nuclear Antigen 3C with Prothymosin Alpha Mol. Cell. Biol., August 1, 2000; 20(15): 5722 - 5735. [Abstract] [Full Text]
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G. L. Bond, C. Prives, and J. L. Manley Poly(A) Polymerase Phosphorylation Is Dependent on Novel Interactions with Cyclins Mol. Cell. Biol., July 15, 2000; 20(14): 5310 - 5320. [Abstract] [Full Text]
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E. Clark, F. Santiago, L. Deng, S. y. Chong, C. de la Fuente, L. Wang, P. Fu, D. Stein, T. Denny, V. Lanka, et al. Loss of G1/S Checkpoint in Human Immunodeficiency Virus Type 1-Infected Cells Is Associated with a Lack of Cyclin-Dependent Kinase Inhibitor p21/Waf1 J. Virol., June 1, 2000; 74(11): 5040 - 5052. [Abstract] [Full Text]
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 A. Mal, D. Chattopadhyay, M. K. Ghosh, R. Y.C. Poon, T. Hunter, and M. L. Harter P21 and Retinoblastoma Protein Control the Absence of DNA Replication in Terminally Differentiated Muscle Cells J. Cell Biol., April 17, 2000; 149(2): 281 - 292. [Abstract] [Full Text] [PDF]
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N. E. Olson, J. Kozlowski, and M. A. Reidy Proliferation of Intimal Smooth Muscle Cells. ATTENUATION OF BASIC FIBROBLAST GROWTH FACTOR 2-STIMULATED PROLIFERATION IS ASSOCIATED WITH INCREASED EXPRESSION OF CELL CYCLE INHIBITORS J. Biol. Chem., April 6, 2000; 275(15): 11270 - 11277. [Abstract] [Full Text] [PDF]
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M. T. Scott, N. Morrice, and K. L. Ball Reversible Phosphorylation at the C-terminal Regulatory Domain of p21Waf1/Cip1 Modulates Proliferating Cell Nuclear Antigen Binding J. Biol. Chem., April 6, 2000; 275(15): 11529 - 11537. [Abstract] [Full Text] [PDF]
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A. Swarbrick, C. S. L. Lee, R. L. Sutherland, and E. A. Musgrove Cooperation of p27Kip1 and p18INK4c in Progestin-Mediated Cell Cycle Arrest in T-47D Breast Cancer Cells Mol. Cell. Biol., April 1, 2000; 20(7): 2581 - 2591. [Abstract] [Full Text]
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 S Siavoshian, J-P Segain, M Kornprobst, C Bonnet, C Cherbut, J-P Galmiche, and H M Blottiere Butyrate and trichostatin A effects on the proliferation/differentiation of human intestinal epithelial cells: induction of cyclin D3 and p21 expression Gut, April 1, 2000; 46(4): 507 - 514. [Abstract] [Full Text] [PDF]
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C. R. Antonescu, D. H. Leung, M. Dudas, M. Ladanyi, M. Brennan, J. M. Woodruff, and C. Cordon-Cardo Alterations of Cell Cycle Regulators in Localized Synovial Sarcoma : A Multifactorial Study with Prognostic Implications Am. J. Pathol., March 1, 2000; 156(3): 977 - 983. [Abstract] [Full Text] [PDF]
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B. Y. Lin, T. Ma, J.-S. Liu, S.-R. Kuo, G. Jin, T. R. Broker, J. W. Harper, and L. T. Chow HeLa Cells Are Phenotypically Limiting in Cyclin E/CDK2 for Efficient Human Papillomavirus DNA Replication J. Biol. Chem., February 25, 2000; 275(9): 6167 - 6174. [Abstract] [Full Text] [PDF]
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E. Suzuki, D. Nagata, M. Yoshizumi, M. Kakoki, A. Goto, M. Omata, and Y. Hirata Reentry into the Cell Cycle of Contact-inhibited Vascular Endothelial Cells by a Phosphatase Inhibitor. POSSIBLE INVOLVEMENT OF EXTRACELLULAR SIGNAL-REGULATED KINASE AND PHOSPHATIDYLINOSITOL 3-KINASE J. Biol. Chem., February 4, 2000; 275(5): 3637 - 3644. [Abstract] [Full Text] [PDF]
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T. Sukata, K. Ozaki, S. Uwagawa, T. Seki, H. Wanibuchi, S. Yamamoto, Y. Okuno, and S. Fukushima Organ-specific, Carcinogen-induced Increases in Cell Proliferation in p53-deficient Mice Cancer Res., January 1, 2000; 60(1): 74 - 79. [Abstract] [Full Text]
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J. Hughes, P. Brown, and S. J. Shankland Cyclin kinase inhibitor p21CIP1/WAF1 limits interstitial cell proliferation following ureteric obstruction Am J Physiol Renal Physiol, December 1, 1999; 277(6): F948 - F956. [Abstract] [Full Text] [PDF]
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Z.-Q. Xiao, Y. Yu, A. Khan, R. Jaszewski, M. N. Ehrinpreis, and A. P. N. Majumdar Induction of G1 checkpoint in the gastric mucosa of aged rats Am J Physiol Gastrointest Liver Physiol, November 1, 1999; 277(5): G929 - G934. [Abstract] [Full Text] [PDF]
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 S. K. Gilmour, M. Birchler, M. K. Smith, K. Rayca, and J. Mostochuk Effect of Elevated Levels of Ornithine Decarboxylase on Cell Cycle Progression in Skin Cell Growth Differ., November 1, 1999; 10(11): 739 - 748. [Abstract] [Full Text]
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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]
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N. Furuno, N. den Elzen, and J. Pines Human Cyclin a Is Required for Mitosis until Mid Prophase J. Cell Biol., October 18, 1999; 147(2): 295 - 306. [Abstract] [Full Text] [PDF]
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M. Baekelandt, R. Holm, C. G. Trope, J. M. Nesland, and G. B. Kristensen Lack of Independent Prognostic Significance of p21 and p27 Expression in Advanced Ovarian Cancer: An Immunohistochemical Study Clin. Cancer Res., October 1, 1999; 5(10): 2848 - 2853. [Abstract] [Full Text] [PDF]
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 R. G. Pestell, C. Albanese, A. T. Reutens, J. E. Segall, R. J. Lee, and A. Arnold The Cyclins and Cyclin-Dependent Kinase Inhibitors in Hormonal Regulation of Proliferation and Differentiation Endocr. Rev., August 1, 1999; 20(4): 501 - 534. [Abstract] [Full Text] [PDF]
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M. Mutoh, F.-D. T. Lung, Y.-Q. Long, P. P. Roller, R. S. Sikorski, and P. M. O'Connor A p21Waf1/Cip1 Carboxyl-terminal Peptide Exhibited Cyclin-dependent Kinase-inhibitory Activity and Cytotoxicity When Introduced into Human Cells Cancer Res., July 1, 1999; 59(14): 3480 - 3488. [Abstract] [Full Text] [PDF]
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 C. J. Sherr and J. M. Roberts CDK inhibitors: positive and negative regulators of G1-phase progression Genes & Dev., June 15, 1999; 13(12): 1501 - 1512. [Full Text]
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 J. Q. Tian and A. Quaroni Involvement of p21(WAF1/Cip1) and p27(Kip1) in intestinal epithelial cell differentiation Am J Physiol Cell Physiol, June 1, 1999; 276(6): C1245 - C1258. [Abstract] [Full Text] [PDF]
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