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Special Lecture |
Howard Hughes Medical Institute and Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105
ABSTRACT
Genetic lesions that disable key regulators of G1 phase progression in mammalian cells are present in most human cancers. Mitogen-dependent, cyclin D-dependent kinases (cdk4 and cdk6) phosphorylate the retinoblastoma (Rb) tumor suppressor protein, helping to cancel its growth-inhibitory effects and enabling E2F transcription factors to activate genes required for entry into the DNA synthetic phase (S) of the cell division cycle. Among the E2F-responsive genes are cyclins E and A, which combine with and activate cdk2 to facilitate S phase entry and progression. Accumulation of cyclin D-dependent kinases during G1 phase sequesters cdk2 inhibitors of the Cip/Kip family, complementing the effects of the E2F transcriptional program by facilitating cyclin E-cdk2 activation at the G1-S transition. Disruption of "the Rb pathway" results from direct mutational inactivation of Rb function, by overexpression of cyclin D-dependent kinases, or through loss of p16INK4a, an inhibitor of the cyclin D-dependent kinases. Reduction in levels of p27Kip1 and increased expression of cyclin E also occur and carry a poor prognostic significance in many common forms of cancer. The ARF tumor suppressor, encoded by an alternative reading frame of the INK4a-ARF locus, senses "mitogenic current" flowing through the Rb pathway and is induced by abnormal growth promoting signals. By antagonizing Mdm2, a negative regulator of the p53 tumor suppressor, ARF triggers a p53-dependent transcriptional response that diverts incipient cancer cells to undergo growth arrest or apoptosis. Although ARF is not directly activated by signals that damage DNA, its loss not only dampens the p53 response to abnormal mitogenic signals but also renders tumor cells resistant to treatment by cytotoxic drugs and irradiation. Lesions in the p16 — cyclin D-CDK4 — Rb and ARF — Mdm2 — p53 pathways occur so frequently in cancer, regardless of patient age or tumor type, that they appear to be part of the life history of most, if not all, cancer cells.
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F. I. Raynaud, S. R. Whittaker, P. M. Fischer, S. McClue, M. I. Walton, S. E. Barrie, M. D. Garrett, P. Rogers, S. J. Clarke, L. R. Kelland, et al. In vitro and In vivo Pharmacokinetic-Pharmacodynamic Relationships for the Trisubstituted Aminopurine Cyclin-Dependent Kinase Inhibitors Olomoucine, Bohemine and CYC202 Clin. Cancer Res., July 1, 2005; 11(13): 4875 - 4887. [Abstract] [Full Text] [PDF]
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O. G. Rodriguez-Mora, M. M. LaHair, J. A. McCubrey, and R. A. Franklin Calcium/Calmodulin-Dependent Kinase I and Calcium/Calmodulin-Dependent Kinase Kinase Participate in the Control of Cell Cycle Progression in MCF-7 Human Breast Cancer Cells Cancer Res., June 15, 2005; 65(12): 5408 - 5416. [Abstract] [Full Text] [PDF]
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C. Bueso-Ramos, Y. Xu, T. J. McDonnell, S. Brisbay, S. Pierce, H. Kantarjian, G. Rosner, and G. Garcia-Manero Protein Expression of a Triad of Frequently Methylated Genes, p73, p57Kip2, and p15, Has Prognostic Value in Adult Acute Lymphocytic Leukemia Independently of Its Methylation Status J. Clin. Oncol., June 10, 2005; 23(17): 3932 - 3939. [Abstract] [Full Text] [PDF]
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J. A. Kushner, M. A. Ciemerych, E. Sicinska, L. M. Wartschow, M. Teta, S. Y. Long, P. Sicinski, and M. F. White Cyclins D2 and D1 Are Essential for Postnatal Pancreatic {beta}-Cell Growth Mol. Cell. Biol., May 1, 2005; 25(9): 3752 - 3762. [Abstract] [Full Text] [PDF]
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R. Sotillo, O. Renner, P. Dubus, J. Ruiz-Cabello, J. Martin-Caballero, M. Barbacid, A. Carnero, and M. Malumbres Cooperation between Cdk4 and p27kip1 in Tumor Development: A Preclinical Model to Evaluate Cell Cycle Inhibitors with Therapeutic Activity Cancer Res., May 1, 2005; 65(9): 3846 - 3852. [Abstract] [Full Text] [PDF]
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L. Tickenbrock, J. Schwable, M. Wiedehage, B. Steffen, B. Sargin, C. Choudhary, C. Brandts, W. E. Berdel, C. Muller-Tidow, and H. Serve Flt3 tandem duplication mutations cooperate with Wnt signaling in leukemic signal transduction Blood, May 1, 2005; 105(9): 3699 - 3706. [Abstract] [Full Text] [PDF]
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I. Perez de Castro, M. Benet, M. Jimenez, S. Alzabin, M. Malumbres, and A. Pellicer Mouse p10, an Alternative Spliced Form of p15INK4b, Inhibits Cell Cycle Progression and Malignant Transformation Cancer Res., April 15, 2005; 65(8): 3249 - 3256. [Abstract] [Full Text] [PDF]
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J. D. Wu, A. Odman, L. M. Higgins, K. Haugk, R. Vessella, D. L. Ludwig, and S. R. Plymate In vivo Effects of the Human Type I Insulin-Like Growth Factor Receptor Antibody A12 on Androgen-Dependent and Androgen-Independent Xenograft Human Prostate Tumors Clin. Cancer Res., April 15, 2005; 11(8): 3065 - 3074. [Abstract] [Full Text] [PDF]
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L. Hernandez, S. Bea, M. Pinyol, G. Ott, T. Katzenberger, A. Rosenwald, F. Bosch, A. Lopez-Guillermo, J. Delabie, D. Colomer, et al. CDK4 and MDM2 Gene Alterations Mainly Occur in Highly Proliferative and Aggressive Mantle Cell Lymphomas with Wild-type INK4a/ARF Locus Cancer Res., March 15, 2005; 65(6): 2199 - 2206. [Abstract] [Full Text] [PDF]
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A. Tanaka, M. Konno, S. Muto, N. Kambe, E. Morii, T. Nakahata, A. Itai, and H. Matsuda A novel NF-{kappa}B inhibitor, IMD-0354, suppresses neoplastic proliferation of human mast cells with constitutively activated c-kit receptors Blood, March 15, 2005; 105(6): 2324 - 2331. [Abstract] [Full Text] [PDF]
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 X. Zhang, J. P. Gaspard, Y. Mizukami, J. Li, F. Graeme-Cook, and D. C. Chung Overexpression of Cyclin D1 in Pancreatic {beta}-Cells In Vivo Results in Islet Hyperplasia Without Hypoglycemia Diabetes, March 1, 2005; 54(3): 712 - 719. [Abstract] [Full Text] [PDF]
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 S.-W. Wang, S.-L. Pan, J.-H. Guh, H.-L. Chen, D.-M. Huang, Y.-L. Chang, S.-C. Kuo, F.-Y. Lee, and C.-M. Teng YC-1 [3-(5'-Hydroxymethyl-2'-furyl)-1-benzyl Indazole] Exhibits a Novel Antiproliferative Effect and Arrests the Cell Cycle in G0-G1 in Human Hepatocellular Carcinoma Cells J. Pharmacol. Exp. Ther., March 1, 2005; 312(3): 917 - 925. [Abstract] [Full Text] [PDF]
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G. Normand, P. G. Hemmati, B. Verdoodt, C. von Haefen, J. Wendt, D. Guner, E. May, B. Dorken, and P. T. Daniel p14ARF Induces G2 Cell Cycle Arrest in p53- and p21-deficient Cells by Down-regulating p34cdc2 Kinase Activity J. Biol. Chem., February 25, 2005; 280(8): 7118 - 7130. [Abstract] [Full Text] [PDF]
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A. Garcia-Espana, E. Salazar, T.-T. Sun, X.-R. Wu, and A. Pellicer Differential Expression of Cell Cycle Regulators in Phenotypic Variants of Transgenically Induced Bladder Tumors: Implications for Tumor Behavior Cancer Res., February 15, 2005; 65(4): 1150 - 1157. [Abstract] [Full Text] [PDF]
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Z. Yu, J. Lin, Y. Xiao, J. Han, X. Zhang, H. Jia, Y. Tang, and Y. Li Induction of Cell-Cycle Arrest by all-trans Retinoic Acid in Mouse Embryonic Palatal Mesenchymal (MEPM) Cells Toxicol. Sci., February 1, 2005; 83(2): 349 - 354. [Abstract] [Full Text] [PDF]
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J. Brzezinski, A. Migodzinski, A. Toczek, J. Tazbir, and M. Dedecjus Patterns of Cyclin E, Retinoblastoma Protein, and p21Cip1/WAF1 Immunostaining in the Oncogenesis of Papillary Thyroid Carcinoma Clin. Cancer Res., February 1, 2005; 11(3): 1037 - 1043. [Abstract] [Full Text] [PDF]
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I. A. Stasinopoulos, Y. Mironchik, A. Raman, F. Wildes, P. Winnard Jr., and V. Raman HOXA5-Twist Interaction Alters p53 Homeostasis in Breast Cancer Cells J. Biol. Chem., January 21, 2005; 280(3): 2294 - 2299. [Abstract] [Full Text] [PDF]
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C. J. Nelsen, R. Kuriyama, B. Hirsch, V. C. Negron, W. L. Lingle, M. M. Goggin, M. W. Stanley, and J. H. Albrecht Short Term Cyclin D1 Overexpression Induces Centrosome Amplification, Mitotic Spindle Abnormalities, and Aneuploidy J. Biol. Chem., January 7, 2005; 280(1): 768 - 776. [Abstract] [Full Text] [PDF]
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 P. WORKMAN Drugging the Cancer Kinome: Progress and Challenges in Developing Personalized Molecular Cancer Therapeutics Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 499 - 515. [Abstract] [PDF]
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J. Vondracek, M. Machala, V. Bryja, K. Chramostova, P. Krcmar, C. Dietrich, A. Hampl, and A. Kozubik Aryl Hydrocarbon Receptor-Activating Polychlorinated Biphenyls and Their Hydroxylated Metabolites Induce Cell Proliferation in Contact-Inhibited Rat Liver Epithelial Cells Toxicol. Sci., January 1, 2005; 83(1): 53 - 63. [Abstract] [Full Text] [PDF]
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M. Fu, C. Wang, Z. Li, T. Sakamaki, and R. G. Pestell Minireview: Cyclin D1: Normal and Abnormal Functions Endocrinology, December 1, 2004; 145(12): 5439 - 5447. [Abstract] [Full Text] [PDF]
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A. H. Box and D. J. Demetrick Cell cycle kinase inhibitor expression and hypoxia-induced cell cycle arrest in human cancer cell lines Carcinogenesis, December 1, 2004; 25(12): 2325 - 2335. [Abstract] [Full Text] [PDF]
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M. Rosner and M. Hengstschlager Tuberin Binds p27 and Negatively Regulates Its Interaction with the SCF Component Skp2 J. Biol. Chem., November 19, 2004; 279(47): 48707 - 48715. [Abstract] [Full Text] [PDF]
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W. Wang, J. Cassidy, V. O'Brien, K. M. Ryan, and E. Collie-Duguid Mechanistic and Predictive Profiling of 5-Fluorouracil Resistance in Human Cancer Cells Cancer Res., November 15, 2004; 64(22): 8167 - 8176. [Abstract] [Full Text] [PDF]
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M. Noseda, L. Chang, G. McLean, J. E. Grim, B. E. Clurman, L. L. Smith, and A. Karsan Notch Activation Induces Endothelial Cell Cycle Arrest and Participates in Contact Inhibition: Role of p21Cip1 Repression Mol. Cell. Biol., October 15, 2004; 24(20): 8813 - 8822. [Abstract] [Full Text] [PDF]
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M. M. Al-Aynati, N. Radulovich, J. Ho, and M.-S. Tsao Overexpression of G1-S Cyclins and Cyclin-Dependent Kinases during Multistage Human Pancreatic Duct Cell Carcinogenesis Clin. Cancer Res., October 1, 2004; 10(19): 6598 - 6605. [Abstract] [Full Text] [PDF]
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J. Wang, T. Wiltshire, Y. Wang, C. Mikell, J. Burks, C. Cunningham, E. S. Van Laar, S. J. Waters, E. Reed, and W. Wang ATM-dependent CHK2 Activation Induced by Anticancer Agent, Irofulven J. Biol. Chem., September 17, 2004; 279(38): 39584 - 39592. [Abstract] [Full Text] [PDF]
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C. C. Leow, M. S. Romero, S. Ross, P. Polakis, and W.-Q. Gao Hath1, Down-Regulated in Colon Adenocarcinomas, Inhibits Proliferation and Tumorigenesis of Colon Cancer Cells Cancer Res., September 1, 2004; 64(17): 6050 - 6057. [Abstract] [Full Text] [PDF]
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D. Tomic, K. P. Miller, H. A. Kenny, T. K. Woodruff, P. Hoyer, and J. A. Flaws Ovarian Follicle Development Requires Smad3 Mol. Endocrinol., September 1, 2004; 18(9): 2224 - 2240. [Abstract] [Full Text] [PDF]
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