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 Mateyak, M. K.
Right arrow Articles by Sedivy, J. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mateyak, M. K.
Right arrow Articles by Sedivy, J. M.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, July 1999, p. 4672-4683, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

c-Myc Regulates Cyclin D-Cdk4 and -Cdk6 Activity but Affects Cell Cycle Progression at Multiple Independent Points

Maria K. Mateyak, Alvaro J. Obaya, and John M. Sedivy*

Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912

Received 2 September 1998/Returned for modification 28 October 1998/Accepted 6 April 1999

c-myc is a cellular proto-oncogene associated with a variety of human cancers and is strongly implicated in the control of cellular proliferation, programmed cell death, and differentiation. We have previously reported the first isolation of a c-myc-null cell line. Loss of c-Myc causes a profound growth defect manifested by the lengthening of both the G1 and G2 phases of the cell cycle. To gain a clearer understanding of the role of c-Myc in cellular proliferation, we have performed a comprehensive analysis of the components that regulate cell cycle progression. The largest defect observed in c-myc-/- cells is a 12-fold reduction in the activity of cyclin D1-Cdk4 and -Cdk6 complexes during the G0-to-S transition. Downstream events, such as activation of cyclin E-Cdk2 and cyclin A-Cdk2 complexes, are delayed and reduced in magnitude. However, it is clear that c-Myc affects the cell cycle at multiple independent points, because restoration of the Cdk4 and -6 defect does not significantly increase growth rate. In exponentially cycling cells the absence of c-Myc reduces coordinately the activities of all cyclin-cyclin-dependent kinase complexes. An analysis of cyclin-dependent kinase complex regulators revealed increased expression of p27KIP1 and decreased expression of Cdk7 in c-myc-/- cells. We propose that c-Myc functions as a crucial link in the coordinate adjustment of growth rate to environmental conditions.

* Corresponding author. Mailing address: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912. Phone: (401) 863-7631. Fax: (401) 863-1201. E-mail: john_sedivy{at}brown.edu.

Molecular and Cellular Biology, July 1999, p. 4672-4683, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Bolisetty, M. T., Dy, G., Tam, W., Beemon, K. L. (2009). Reticuloendotheliosis Virus Strain T Induces miR-155, Which Targets JARID2 and Promotes Cell Survival. J. Virol. 83: 12009-12017 [Abstract] [Full Text]  
  • Rohan, J. N. P., Weigel, N. L. (2009). 1{alpha},25-Dihydroxyvitamin D3 Reduces c-Myc Expression, Inhibiting Proliferation and Causing G1 Accumulation in C4-2 Prostate Cancer Cells. Endocrinology 150: 2046-2054 [Abstract] [Full Text]  
  • Niapour, M., Yu, Y., Berger, S. A. (2008). Regulation of Calpain Activity by c-Myc through Calpastatin and Promotion of Transformation in c-Myc-negative Cells by Calpastatin Suppression. J. Biol. Chem. 283: 21371-21381 [Abstract] [Full Text]  
  • Marques, M., Kumar, A., Cortes, I., Gonzalez-Garcia, A., Hernandez, C., Moreno-Ortiz, M. C., Carrera, A. C. (2008). Phosphoinositide 3-Kinases p110{alpha} and p110{beta} Regulate Cell Cycle Entry, Exhibiting Distinct Activation Kinetics in G1 Phase. Mol. Cell. Biol. 28: 2803-2814 [Abstract] [Full Text]  
  • Liao, W.-R., Hsieh, R.-H., Hsu, K.-W., Wu, M.-Z., Tseng, M.-J., Mai, R.-T., Wu Lee, Y.-H., Yeh, T.-S. (2007). The CBF1-independent Notch1 signal pathway activates human c-myc expression partially via transcription factor YY1. Carcinogenesis 28: 1867-1876 [Abstract] [Full Text]  
  • Cowling, V. H., Cole, M. D. (2007). The Myc Transactivation Domain Promotes Global Phosphorylation of the RNA Polymerase II Carboxy-Terminal Domain Independently of Direct DNA Binding. Mol. Cell. Biol. 27: 2059-2073 [Abstract] [Full Text]  
  • Kumar, A., Marques, M., Carrera, A. C. (2006). Phosphoinositide 3-Kinase Activation in Late G1 Is Required for c-Myc Stabilization and S Phase Entry. Mol. Cell. Biol. 26: 9116-9125 [Abstract] [Full Text]  
  • Groisman, I., Ivshina, M., Marin, V., Kennedy, N. J., Davis, R. J., Richter, J. D. (2006). Control of cellular senescence by CPEB. Genes Dev. 20: 2701-2712 [Abstract] [Full Text]  
  • Ou, X.-M., Chen, K., Shih, J. C. (2006). Monoamine oxidase A and repressor R1 are involved in apoptotic signaling pathway. Proc. Natl. Acad. Sci. USA 103: 10923-10928 [Abstract] [Full Text]  
  • Bianchi, T., Gasser, S., Trumpp, A., MacDonald, H. R. (2006). c-Myc acts downstream of IL-15 in the regulation of memory CD8 T-cell homeostasis. Blood 107: 3992-3999 [Abstract] [Full Text]  
  • Dezfouli, S., Bakke, A., Huang, J., Wynshaw-Boris, A., Hurlin, P. J. (2006). Inflammatory disease and lymphomagenesis caused by deletion of the myc antagonist mnt in T cells.. Mol. Cell. Biol. 26: 2080-2092 [Abstract] [Full Text]  
  • Prathapam, T., Tegen, S., Oskarsson, T., Trumpp, A., Martin, G. S. (2006). Activated Src abrogates the Myc requirement for the G0/G1 transition but not for the G1/S transition. Proc. Natl. Acad. Sci. USA 103: 2695-2700 [Abstract] [Full Text]  
  • Skaletz-Rorowski, A., Eschert, H., Leng, J., Stallmeyer, B., Sindermann, J. R., Pulawski, E., Breithardt, G. (2005). PKC {delta}-induced activation of MAPK pathway is required for bFGF-stimulated proliferation of coronary smooth muscle cells. Cardiovasc Res 67: 142-150 [Abstract] [Full Text]  
  • Munoz-Alonso, M. J., Acosta, J. C., Richard, C., Delgado, M. D., Sedivy, J., Leon, J. (2005). p21Cip1 and p27Kip1 Induce Distinct Cell Cycle Effects and Differentiation Programs in Myeloid Leukemia Cells. J. Biol. Chem. 280: 18120-18129 [Abstract] [Full Text]  
  • Gil, J., Kerai, P., Lleonart, M., Bernard, D., Cigudosa, J. C., Peters, G., Carnero, A., Beach, D. (2005). Immortalization of Primary Human Prostate Epithelial Cells by c-Myc. Cancer Res. 65: 2179-2185 [Abstract] [Full Text]  
  • Kaburagi, Y., Yamashita, R., Ito, Y., Okochi, H., Yamamoto-Honda, R., Yasuda, K., Sekihara, H., Sasazuki, T., Kadowaki, T., Yazaki, Y. (2004). Insulin-Induced Cell Cycle Progression Is Impaired in Chinese Hamster Ovary Cells Overexpressing Insulin Receptor Substrate-3. Endocrinology 145: 5862-5874 [Abstract] [Full Text]  
  • Blum, K. A., Lozanski, G., Byrd, J. C. (2004). Adult Burkitt leukemia and lymphoma. Blood 104: 3009-3020 [Abstract] [Full Text]  
  • Gonzalez-Cabrera, P. J., Shi, T., Yun, J., McCune, D. F., Rorabaugh, B. R., Perez, D. M. (2004). Differential Regulation of the Cell Cycle by {alpha}1-Adrenergic Receptor Subtypes. Endocrinology 145: 5157-5167 [Abstract] [Full Text]  
  • Satoh, Y., Matsumura, I., Tanaka, H., Ezoe, S., Sugahara, H., Mizuki, M., Shibayama, H., Ishiko, E., Ishiko, J., Nakajima, K., Kanakura, Y. (2004). Roles for c-Myc in Self-renewal of Hematopoietic Stem Cells. J. Biol. Chem. 279: 24986-24993 [Abstract] [Full Text]  
  • Fan, X., Liu, Y., Chen, J. J. (2003). Activation of c-Myc Contributes to Bovine Papillomavirus Type 1 E7-induced Cell Proliferation. J. Biol. Chem. 278: 43163-43168 [Abstract] [Full Text]  
  • Tsutsumi, S., Yanagawa, T., Shimura, T., Fukumori, T., Hogan, V., Kuwano, H., Raz, A. (2003). Regulation of Cell Proliferation by Autocrine Motility Factor/Phosphoglucose Isomerase Signaling. J. Biol. Chem. 278: 32165-32172 [Abstract] [Full Text]  
  • O'Connell, B. C., Cheung, A. F., Simkevich, C. P., Tam, W., Ren, X., Mateyak, M. K., Sedivy, J. M. (2003). A Large Scale Genetic Analysis of c-Myc-regulated Gene Expression Patterns. J. Biol. Chem. 278: 12563-12573 [Abstract] [Full Text]  
  • Schorl, C., Sedivy, J. M. (2003). Loss of Protooncogene c-Myc Function Impedes G1 Phase Progression Both before and after the Restriction Point. Mol. Biol. Cell 14: 823-835 [Abstract] [Full Text]  
  • Donovan, J. C. H., Rothenstein, J. M., Slingerland, J. M. (2002). Non-malignant and Tumor-derived Cells Differ in Their Requirement for p27Kip1 in Transforming Growth Factor-beta -mediated G1 Arrest. J. Biol. Chem. 277: 41686-41692 [Abstract] [Full Text]  
  • Leoncini, L, Lazzi, S, Bellan, C, Tosi, P (2002). Cell kinetics and cell cycle regulation in lymphomas. J. Clin. Pathol. 55: 648-655 [Abstract] [Full Text]  
  • Obaya, A. J., Kotenko, I., Cole, M. D., Sedivy, J. M. (2002). The Proto-oncogene c-myc Acts through the Cyclin-dependent Kinase (Cdk) Inhibitor p27Kip1 to Facilitate the Activation of Cdk4/6 and Early G1 Phase Progression. J. Biol. Chem. 277: 31263-31269 [Abstract] [Full Text]  
  • Demeterco, C., Itkin-Ansari, P., Tyrberg, B., Ford, L. P., Jarvis, R. A., Levine, F. (2002). c-Myc Controls Proliferation Versus Differentiation in Human Pancreatic Endocrine Cells. J. Clin. Endocrinol. Metab. 87: 3475-3485 [Abstract] [Full Text]  
  • Walter, K. A., Hossain, M. A., Luddy, C., Goel, N., Reznik, T. E., Laterra, J. (2002). Scatter Factor/Hepatocyte Growth Factor Stimulation of Glioblastoma Cell Cycle Progression through G1 Is c-Myc Dependent and Independent of p27 Suppression, Cdk2 Activation, or E2F1-Dependent Transcription. Mol. Cell. Biol. 22: 2703-2715 [Abstract] [Full Text]  
  • Piedra, M. E., Delgado, M. D., Ros, M. A., Leon, J. (2002). c-Myc Overexpression Increases Cell Size and Impairs Cartilage Differentiation during Chick Limb Development. Cell Growth Differ. 13: 185-193 [Abstract] [Full Text]  
  • Cerezo, A., Kalthoff, H., Schuermann, M., Schafer, B., Boukamp, P. (2002). Dual regulation of telomerase activity through c-Myc-dependent inhibition and alternative splicing of hTERT. J. Cell Sci. 115: 1305-1312 [Abstract] [Full Text]  
  • Yagi, K., Furuhashi, M., Aoki, H., Goto, D., Kuwano, H., Sugamura, K., Miyazono, K., Kato, M. (2002). c-myc Is a Downstream Target of the Smad Pathway. J. Biol. Chem. 277: 854-861 [Abstract] [Full Text]  
  • Adachi, S., Obaya, A. J., Han, Z., Ramos-Desimone, N., Wyche, J. H., Sedivy, J. M. (2001). c-Myc Is Necessary for DNA Damage-Induced Apoptosis in the G2 Phase of the Cell Cycle. Mol. Cell. Biol. 21: 4929-4937 [Abstract] [Full Text]  
  • Soucie, E. L., Annis, M. G., Sedivy, J., Filmus, J., Leber, B., Andrews, D. W., Penn, L. Z. (2001). Myc Potentiates Apoptosis by Stimulating Bax Activity at the Mitochondria. Mol. Cell. Biol. 21: 4725-4736 [Abstract] [Full Text]  
  • Bazarov, A. V., Adachi, S., Li, S.-F., Mateyak, M. K., Wei, S., Sedivy, J. M. (2001). A Modest Reduction in c-Myc Expression Has Minimal Effects on Cell Growth and Apoptosis But Dramatically Reduces Susceptibility to Ras and Raf Transformation. Cancer Res. 61: 1178-1186 [Abstract] [Full Text]  
  • Lin, K.-I, Lin, Y., Calame, K. (2000). Repression of c-myc Is Necessary but Not Sufficient for Terminal Differentiation of B Lymphocytes In Vitro. Mol. Cell. Biol. 20: 8684-8695 [Abstract] [Full Text]  
  • Brantley, M. A. Jr., Harbour, J. W. (2000). Deregulation of the Rb and p53 Pathways in Uveal Melanoma. Am. J. Pathol. 157: 1795-1801 [Abstract] [Full Text]  
  • Hecht, J. L., Aster, J. C. (2000). Molecular Biology of Burkitt's Lymphoma. JCO 18: 3707-3721 [Abstract] [Full Text]  
  • Ravanko, K., Järvinen, K., Paasinen-Sohns, A., Hölttä, E. (2000). Loss of p27Kip1 from Cyclin E/Cyclin-dependent Kinase (CDK) 2 but not from Cyclin D1/CDK4 Complexes in Cells Transformed by Polyamine Biosynthetic Enzymes. Cancer Res. 60: 5244-5253 [Abstract] [Full Text]  
  • O'Hagan, R. C., Ohh, M., David, G., de Alboran, I. M., Alt, F. W., Kaelin, W. G. Jr., DePinho, R. A. (2000). Myc-enhanced expression of Cul1 promotes ubiquitin-dependent proteolysis and cell cycle progression. Genes Dev. 14: 2185-2191 [Abstract] [Full Text]  
  • Willis, T. G., Dyer, M. J. S. (2000). The role of immunoglobulin translocations in the pathogenesis of B-cell malignancies. Blood 96: 808-822 [Full Text]  
  • Volarevic, S., Stewart, M. J., Ledermann, B., Zilberman, F., Terracciano, L., Montini, E., Grompe, M., Kozma, S. C., Thomas, G. (2000). Proliferation, But Not Growth, Blocked by Conditional Deletion of 40S Ribosomal Protein S6. Science 288: 2045-2047 [Abstract] [Full Text]  
  • Stepanova, L., Finegold, M., DeMayo, F., Schmidt, E. V., Harper, J. W. (2000). The Oncoprotein Kinase Chaperone CDC37 Functions as an Oncogene in Mice and Collaborates with Both c-myc and Cyclin D1 in Transformation of Multiple Tissues. Mol. Cell. Biol. 20: 4462-4473 [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]  
  • Quéva, C., McArthur, G. A., Ramos, L. S., Eisenman, R. N. (1999). Dwarfism and Dysregulated Proliferation in Mice Overexpressing the MYC Antagonist MAD1. Cell Growth Differ. 10: 785-796 [Abstract] [Full Text]  
  • Donjerkovic, D., Zhang, L., Scott, D. W. (1999). Regulation of p27Kip1 Accumulation in Murine B-Lymphoma Cells: Role of c-Myc and Calcium. Cell Growth Differ. 10: 695-704 [Abstract] [Full Text]  
  • Hermeking, H., Rago, C., Schuhmacher, M., Li, Q., Barrett, J. F., Obaya, A. J., O'Connell, B. C., Mateyak, M. K., Tam, W., Kohlhuber, F., Dang, C. V., Sedivy, J. M., Eick, D., Vogelstein, B., Kinzler, K. W. (2000). Identification of CDK4 as a target of c-MYC. Proc. Natl. Acad. Sci. USA 97: 2229-2234 [Abstract] [Full Text]  
  • Gartel, A. L., Ye, X., Goufman, E., Shianov, P., Hay, N., Najmabadi, F., Tyner, A. L. (2001). Myc represses the p21(WAF1/CIP1) promoter and interacts with Sp1/Sp3. Proc. Natl. Acad. Sci. USA 98: 4510-4515 [Abstract] [Full Text]  
  • Bowman, T., Broome, M. A., Sinibaldi, D., Wharton, W., Pledger, W. J., Sedivy, J. M., Irby, R., Yeatman, T., Courtneidge, S. A., Jove, R. (2001). Stat3-mediated Myc expression is required for Src transformation and PDGF-induced mitogenesis. Proc. Natl. Acad. Sci. USA 98: 7319-7324 [Abstract] [Full Text]  
  • Claassen, G. F., Hann, S. R. (2000). A role for transcriptional repression of p21CIP1 by c-Myc in overcoming transforming growth factor beta -induced cell-cycle arrest. Proc. Natl. Acad. Sci. USA 97: 9498-9503 [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»