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 Slomiany, B. A.
Right arrow Articles by Kurtz, D. T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Slomiany, B. A.
Right arrow Articles by Kurtz, D. T.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, August 2000, p. 5986-5997, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

C/EBPalpha Inhibits Cell Growth via Direct Repression of E2F-DP-Mediated Transcription

Beatrix A. Slomiany,1,2 Kenneth L. D'Arigo,1 Margaret M. Kelly,1,dagger and David T. Kurtz1,2,*

Department of Pharmacology1 and the Environmental Biosciences Program,2 Medical University of South Carolina, Charleston, South Carolina 29425

Received 20 December 1999/Returned for modification 27 January 2000/Accepted 23 May 2000

Using an inducible transcription system which allows the regulated expression of C/EBP isoforms in tissue culture cells, we have found that the ectopic expression of C/EBPalpha , at a level comparable to that found in normal liver tissue, has a pronounced antimitogenic effect in mouse L cells and NIH 3T3 cells. The inhibition of cell division by C/EBPalpha in mouse cells cannot be reversed by simian virus 40 T antigen, by oncogenic ras, or by adenovirus E1a protein. When expressed in thymidine kinase-deficient L cells or 3T3 cells, C/EBPalpha is detected in a protein complex which binds to the E2F binding sites found in the promoters of the genes for E2F-1 and dihydrofolate reductase (DHFR). Bacterially expressed C/EBPalpha has no affinity for these E2F sites, but when recombinant C/EBPalpha is added to nuclear extracts from mouse fibroblasts, a new E2F binding activity appears, which contains the C/EBPalpha protein. Using an E2F-DP1-responsive promoter linked to a reporter gene, it can be shown that C/EBPalpha directly inhibits the induction of this promoter by E2F-DP1 in transient-transfection assays. Furthermore, C/EBPalpha can be shown to inhibit the S-phase induction of the E2F and DHFR promoters in permanent cell lines. These findings delineate a straightforward mechanism for C/EBPalpha -mediated cell growth arrest through repression of E2F-DP-mediated S-phase transcription.

* Corresponding author. Mailing address: Department of Pharmacology, Medical University of South Carolina, Charleston, South Carolina 29425. Phone: (843) 792-5844. Fax: (843) 792-2475. E-mail: kurtzdt{at}musc.edu.

dagger Present address: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425.

Molecular and Cellular Biology, August 2000, p. 5986-5997, Vol. 20, No. 16
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Koschmieder, S., Halmos, B., Levantini, E., Tenen, D. G. (2009). Dysregulation of the C/EBP{alpha} Differentiation Pathway in Human Cancer. JCO 27: 619-628 [Abstract] [Full Text]  
  • Dhawan, P., Weider, R., Christakos, S. (2009). CCAAT Enhancer-binding Protein {alpha} Is a Molecular Target of 1,25-Dihydroxyvitamin D3 in MCF-7 Breast Cancer Cells. J. Biol. Chem. 284: 3086-3095 [Abstract] [Full Text]  
  • Seifeddine, R., Dreiem, A., Blanc, E., Fulchignoni-Lataud, M.-C., Belda, M.-A. L. F., Lecuru, F., Mayi, T. H., Mazure, N., Favaudon, V., Massaad, C., Barouki, R., Massaad-Massade, L. (2008). Hypoxia Down-regulates CCAAT/Enhancer Binding Protein-{alpha} Expression in Breast Cancer Cells. Cancer Res. 68: 2158-2165 [Abstract] [Full Text]  
  • Wang, H., Larris, B., Peiris, T. H., Zhang, L., Le Lay, J., Gao, Y., Greenbaum, L. E. (2007). C/EBPbeta Activates E2F-regulated Genes in Vivo via Recruitment of the Coactivator CREB-binding Protein/P300. J. Biol. Chem. 282: 24679-24688 [Abstract] [Full Text]  
  • Loomis, K. D., Zhu, S., Yoon, K., Johnson, P. F., Smart, R. C. (2007). Genetic Ablation of CCAAT/Enhancer Binding Protein {alpha} in Epidermis Reveals Its Role in Suppression of Epithelial Tumorigenesis. Cancer Res. 67: 6768-6776 [Abstract] [Full Text]  
  • Hatzis, P., Kyrmizi, I., Talianidis, I. (2006). Mitogen-Activated Protein Kinase-Mediated Disruption of Enhancer-Promoter Communication Inhibits Hepatocyte Nuclear Factor 4{alpha} Expression.. Mol. Cell. Biol. 26: 7017-7029 [Abstract] [Full Text]  
  • Ferrari-Amorotti, G., Keeshan, K., Zattoni, M., Guerzoni, C., Iotti, G., Cattelani, S., Donato, N. J., Calabretta, B. (2006). Leukemogenesis induced by wild-type and STI571-resistant BCR/ABL is potently suppressed by C/EBP{alpha}. Blood 108: 1353-1362 [Abstract] [Full Text]  
  • Sato, Y., Miyake, K., Kaneoka, H., Iijima, S. (2006). Sumoylation of CCAAT/Enhancer-binding Protein {alpha} and Its Functional Roles in Hepatocyte Differentiation. J. Biol. Chem. 281: 21629-21639 [Abstract] [Full Text]  
  • Xu, Y., Zhou, Y. L., Luo, W., Zhu, Q.-S., Levy, D., MacDougald, O. A., Snead, M. L. (2006). NF-Y and CCAAT/Enhancer-binding Protein {alpha} Synergistically Activate the Mouse Amelogenin Gene. J. Biol. Chem. 281: 16090-16098 [Abstract] [Full Text]  
  • Wierenga, A. T. J., Schepers, H., Moore, M. A. S., Vellenga, E., Schuringa, J. J. (2006). STAT5-induced self-renewal and impaired myelopoiesis of human hematopoietic stem/progenitor cells involves down-modulation of C/EBP{alpha}. Blood 107: 4326-4333 [Abstract] [Full Text]  
  • Suh, H. C., Gooya, J., Renn, K., Friedman, A. D., Johnson, P. F., Keller, J. R. (2006). C/EBP{alpha} determines hematopoietic cell fate in multipotential progenitor cells by inhibiting erythroid differentiation and inducing myeloid differentiation. Blood 107: 4308-4316 [Abstract] [Full Text]  
  • Chattopadhyay, S., Gong, E.-Y., Hwang, M., Park, E., Lee, H. J., Hong, C. Y., Choi, H.-S., Cheong, J.-H., Kwon, H. B., Lee, K. (2006). The CCAAT Enhancer-Binding Protein-{alpha} Negatively Regulates the Transactivation of Androgen Receptor in Prostate Cancer Cells. Mol. Endocrinol. 20: 984-995 [Abstract] [Full Text]  
  • Ikeda, H., Omoteyama, K., Yoshida, K., Nishi, S., Sakai, M. (2006). CCAAT Enhancer-binding Protein {alpha} Suppresses the Rat Placental Glutathione S-Transferase Gene in Normal Liver. J. Biol. Chem. 281: 6734-6741 [Abstract] [Full Text]  
  • Porse, B. T., Pedersen, T. A., Hasemann, M. S., Schuster, M. B., Kirstetter, P., Luedde, T., Damgaard, I., Kurz, E., Schjerling, C. K., Nerlov, C. (2006). The Proline-Histidine-Rich CDK2/CDK4 Interaction Region of C/EBP{alpha} Is Dispensable for C/EBP{alpha}-Mediated Growth Regulation In Vivo. Mol. Cell. Biol. 26: 1028-1037 [Abstract] [Full Text]  
  • Basseres, D. S., Levantini, E., Ji, H., Monti, S., Elf, S., Dayaram, T., Fenyus, M., Kocher, O., Golub, T., Wong, K.-k., Halmos, B., Tenen, D. G. (2006). Respiratory Failure Due to Differentiation Arrest and Expansion of Alveolar Cells following Lung-Specific Loss of the Transcription Factor C/EBP{alpha} in Mice. Mol. Cell. Biol. 26: 1109-1123 [Abstract] [Full Text]  
  • Porse, B. T., Bryder, D., Theilgaard-Monch, K., Hasemann, M. S., Anderson, K., Damgaard, I., Jacobsen, S. E. W., Nerlov, C. (2005). Loss of C/EBP{alpha} cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage. JEM 202: 85-96 [Abstract] [Full Text]  
  • Johnson, P. F. (2005). Molecular stop signs: regulation of cell-cycle arrest by C/EBP transcription factors. J. Cell Sci. 118: 2545-2555 [Abstract] [Full Text]  
  • Takai, N., Kawamata, N., Walsh, C. S., Gery, S., Desmond, J. C., Whittaker, S., Said, J. W., Popoviciu, L. M., Jones, P. A., Miyakawa, I., Koeffler, H. P. (2005). Discovery of Epigenetically Masked Tumor Suppressor Genes in Endometrial Cancer. Mol Cancer Res 3: 261-269 [Abstract] [Full Text]  
  • Gery, S., Tanosaki, S., Bose, S., Bose, N., Vadgama, J., Koeffler, H. P. (2005). Down-Regulation and Growth Inhibitory Role of C/EBP{alpha} in Breast Cancer. Clin. Cancer Res. 11: 3184-3190 [Abstract] [Full Text]  
  • Shim, M., Powers, K. L., Ewing, S. J., Zhu, S., Smart, R. C. (2005). Diminished Expression of C/EBP{alpha} in Skin Carcinomas Is Linked to Oncogenic Ras and Reexpression of C/EBP{alpha} in Carcinoma Cells Inhibits Proliferation. Cancer Res. 65: 861-867 [Abstract] [Full Text]  
  • Yoon, K., Smart, R. C. (2004). C/EBP{alpha} Is a DNA Damage-Inducible p53-Regulated Mediator of the G1 Checkpoint in Keratinocytes. Mol. Cell. Biol. 24: 10650-10660 [Abstract] [Full Text]  
  • Zhang, Y., Hamburger, A. W. (2004). Heregulin Regulates the Ability of the ErbB3-binding Protein Ebp1 to Bind E2F Promoter Elements and Repress E2F-mediated Transcription. J. Biol. Chem. 279: 26126-26133 [Abstract] [Full Text]  
  • Schrem, H., Klempnauer, J., Borlak, J. (2004). Liver-Enriched Transcription Factors in Liver Function and Development. Part II: the C/EBPs and D Site-Binding Protein in Cell Cycle Control, Carcinogenesis, Circadian Gene Regulation, Liver Regeneration, Apoptosis, and Liver-Specific Gene Regulation. Pharmacol. Rev. 56: 291-330 [Abstract] [Full Text]  
  • Panguluri, R. C.K., Long, L. O., Chen, W., Wang, S., Coulibaly, A., Ukoli, F., Jackson, A., Weinrich, S., Ahaghotu, C., Isaacs, W., Kittles, R. A. (2004). COX-2 gene promoter haplotypes and prostate cancer risk. Carcinogenesis 25: 961-966 [Abstract] [Full Text]  
  • Wu, F. Y., Wang, S. E., Chen, H., Wang, L., Hayward, S. D., Hayward, G. S. (2004). CCAAT/Enhancer Binding Protein {alpha} Binds to the Epstein-Barr Virus (EBV) ZTA Protein through Oligomeric Interactions and Contributes to Cooperative Transcriptional Activation of the ZTA Promoter through Direct Binding to the ZII and ZIIIB Motifs during Induction of the EBV Lytic Cycle. J. Virol. 78: 4847-4865 [Abstract] [Full Text]  
  • Frolov, M. V., Dyson, N. J. (2004). Molecular mechanisms of E2F-dependent activation and pRB-mediated repression. J. Cell Sci. 117: 2173-2181 [Abstract] [Full Text]  
  • Schwieger, M., Lohler, J., Fischer, M., Herwig, U., Tenen, D. G., Stocking, C. (2004). A dominant-negative mutant of C/EBP{alpha}, associated with acute myeloid leukemias, inhibits differentiation of myeloid and erythroid progenitors of man but not mouse. Blood 103: 2744-2752 [Abstract] [Full Text]  
  • Muller, C., Calkhoven, C. F., Sha, X., Leutz, A. (2004). The CCAAT Enhancer-binding Protein {alpha} (C/EBP{alpha}) Requires a SWI/SNF Complex for Proliferation Arrest. J. Biol. Chem. 279: 7353-7358 [Abstract] [Full Text]  
  • Gery, S., Gombart, A. F., Fung, Y. K., Koeffler, H. P. (2004). C/EBP{epsilon} interacts with retinoblastoma and E2F1 during granulopoiesis. Blood 103: 828-835 [Abstract] [Full Text]  
  • Ross, S. E., Radomska, H. S., Wu, B., Zhang, P., Winnay, J. N., Bajnok, L., Wright, W. S., Schaufele, F., Tenen, D. G., MacDougald, O. A. (2004). Phosphorylation of C/EBP{alpha} Inhibits Granulopoiesis. Mol. Cell. Biol. 24: 675-686 [Abstract] [Full Text]  
  • Marabese, M., Vikhanskaya, F., Rainelli, C., Sakai, T., Broggini, M. (2003). DNA damage induces transcriptional activation of p73 by removing C-EBP{alpha} repression on E2F1. Nucleic Acids Res 31: 6624-6632 [Abstract] [Full Text]  
  • D'Alo', F., Johansen, L. M., Nelson, E. A., Radomska, H. S., Evans, E. K., Zhang, P., Nerlov, C., Tenen, D. G. (2003). The amino terminal and E2F interaction domains are critical for C/EBP{alpha}-mediated induction of granulopoietic development of hematopoietic cells. Blood 102: 3163-3171 [Abstract] [Full Text]  
  • Gagliardi, M., Maynard, S., Miyake, T., Rodrigues, N., Tjew, S. L., Cabannes, E., Bedard, P.-A. (2003). Opposing Roles of C/EBP{beta} and AP-1 in the Control of Fibroblast Proliferation and Growth Arrest-specific Gene Expression. J. Biol. Chem. 278: 43846-43854 [Abstract] [Full Text]  
  • Wang, S. E., Wu, F. Y., Yu, Y., Hayward, G. S. (2003). CCAAT/Enhancer-Binding Protein-{alpha} Is Induced during the Early Stages of Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Lytic Cycle Reactivation and Together with the KSHV Replication and Transcription Activator (RTA) Cooperatively Stimulates the Viral RTA, MTA, and PAN Promoters. J. Virol. 77: 9590-9612 [Abstract] [Full Text]  
  • Wu, F. Y., Wang, S. E., Tang, Q.-Q., Fujimuro, M., Chiou, C.-J., Zheng, Q., Chen, H., Hayward, S. D., Lane, M. D., Hayward, G. S. (2003). Cell Cycle Arrest by Kaposi's Sarcoma-Associated Herpesvirus Replication-Associated Protein Is Mediated at both the Transcriptional and Posttranslational Levels by Binding to CCAAT/Enhancer-Binding Protein {alpha} and p21CIP-1. J. Virol. 77: 8893-8914 [Abstract] [Full Text]  
  • Keeshan, K., Santilli, G., Corradini, F., Perrotti, D., Calabretta, B. (2003). Transcription activation function of C/EBP{alpha} is required for induction of granulocytic differentiation. Blood 102: 1267-1275 [Abstract] [Full Text]  
  • Miller, M., Shuman, J. D., Sebastian, T., Dauter, Z., Johnson, P. F. (2003). Structural Basis for DNA Recognition by the Basic Region Leucine Zipper Transcription Factor CCAAT/Enhancer-binding Protein alpha. J. Biol. Chem. 278: 15178-15184 [Abstract] [Full Text]  
  • Cammenga, J., Mulloy, J. C., Berguido, F. J., MacGrogan, D., Viale, A., Nimer, S. D. (2003). Induction of C/EBPalpha activity alters gene expression and differentiation of human CD34+ cells. Blood 101: 2206-2214 [Abstract] [Full Text]  
  • Landsberg, R. L., Sero, J. E., Danielian, P. S., Yuan, T. L., Lee, E. Y., Lees, J. A. (2003). The role of E2F4 in adipogenesis is independent of its cell cycle regulatory activity. Proc. Natl. Acad. Sci. USA 100: 2456-2461 [Abstract] [Full Text]  
  • Gigliotti, A. P., Johnson, P. F., Sterneck, E., DeWille, J. W. (2003). Nulliparous CCAAT/Enhancer Binding Protein{delta} (C/EBP{delta}) Knockout Mice Exhibit Mammary Gland Ductal Hyperlasia. Exp. Biol. Med. 228: 278-285 [Abstract] [Full Text]  
  • Truong, B.-T. H., Lee, Y.-J., Lodie, T. A., Park, D. J., Perrotti, D., Watanabe, N., Koeffler, H. P., Nakajima, H., Tenen, D. G., Kogan, S. C. (2003). CCAAT/Enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia. Blood 101: 1141-1148 [Abstract] [Full Text]  
  • Wu, F. Y., Chen, H., Wang, S. E., apRhys, C. M. J., Liao, G., Fujimuro, M., Farrell, C. J., Huang, J., Hayward, S. D., Hayward, G. S. (2002). CCAAT/Enhancer Binding Protein {alpha} Interacts with ZTA and Mediates ZTA-Induced p21CIP-1 Accumulation and G1 Cell Cycle Arrest during the Epstein-Barr Virus Lytic Cycle. J. Virol. 77: 1481-1500 [Abstract] [Full Text]  
  • Wang, S. E., Wu, F. Y., Fujimuro, M., Zong, J., Hayward, S. D., Hayward, G. S. (2002). Role of CCAAT/Enhancer-Binding Protein Alpha (C/EBP{alpha}) in Activation of the Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Lytic-Cycle Replication-Associated Protein (RAP) Promoter in Cooperation with the KSHV Replication and Transcription Activator (RTA) and RAP. J. Virol. 77: 600-623 [Abstract] [Full Text]  
  • Wu, F. Y., Tang, Q.-Q., Chen, H., ApRhys, C., Farrell, C., Chen, J., Fujimuro, M., Lane, M. D., Hayward, G. S. (2002). Lytic replication-associated protein (RAP) encoded by Kaposi sarcoma-associated herpesvirus causes p21CIP-1-mediated G1 cell cycle arrest through CCAAT/enhancer-binding protein-alpha. Proc. Natl. Acad. Sci. USA 99: 10683-10688 [Abstract] [Full Text]  
  • Behre, G., Singh, S. M., Liu, H., Bortolin, L. T., Christopeit, M., Radomska, H. S., Rangatia, J., Hiddemann, W., Friedman, A. D., Tenen, D. G. (2002). Ras Signaling Enhances the Activity of C/EBPalpha to Induce Granulocytic Differentiation by Phosphorylation of Serine 248. J. Biol. Chem. 277: 26293-26299 [Abstract] [Full Text]  
  • Wang, Q.-f., Friedman, A. D. (2002). CCAAT/enhancer-binding proteins are required for granulopoiesis independent of their induction of the granulocyte colony-stimulating factor receptor. Blood 99: 2776-2785 [Abstract] [Full Text]  
  • Wells, J., Graveel, C. R., Bartley, S. M., Madore, S. J., Farnham, P. J. (2002). The identification of E2F1-specific target genes. Proc. Natl. Acad. Sci. USA 99: 3890-3895 [Abstract] [Full Text]  
  • Lei, N., Heckert, L. L. (2002). Sp1 and Egr1 Regulate Transcription of the Dmrt1 Gene in Sertoli Cells. Biol. Reprod. 66: 675-684 [Abstract] [Full Text]  
  • Gombart, A. F., Hofmann, W.-K., Kawano, S., Takeuchi, S., Krug, U., Kwok, S. H., Larsen, R. J., Asou, H., Miller, C. W., Hoelzer, D., Koeffler, H. P. (2002). Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias. Blood 99: 1332-1340 [Abstract] [Full Text]  
  • Halmos, B., Huettner, C. S., Kocher, O., Ferenczi, K., Karp, D. D., Tenen, D. G. (2002). Down-Regulation and Antiproliferative Role of C/EBP{alpha} in Lung Cancer. Cancer Res. 62: 528-534 [Abstract] [Full Text]  
  • Gheorghiu, I., Deschenes, C., Blais, M., Boudreau, F., Rivard, N., Asselin, C. (2001). Role of Specific CCAAT/Enhancer-binding Protein Isoforms in Intestinal Epithelial Cells. J. Biol. Chem. 276: 44331-44337 [Abstract] [Full Text]  
  • Weinmann, A. S., Bartley, S. M., Zhang, T., Zhang, M. Q., Farnham, P. J. (2001). Use of Chromatin Immunoprecipitation To Clone Novel E2F Target Promoters. Mol. Cell. Biol. 21: 6820-6832 [Abstract] [Full Text]  
  • Johansen, L. M., Iwama, A., Lodie, T. A., Sasaki, K., Felsher, D. W., Golub, T. R., Tenen, D. G. (2001). c-Myc Is a Critical Target for C/EBP{alpha} in Granulopoiesis. Mol. Cell. Biol. 21: 3789-3806 [Abstract] [Full Text]  
  • Harris, T. E., Albrecht, J. H., Nakanishi, M., Darlington, G. J. (2001). CCAAT/Enhancer-binding Protein-alpha Cooperates with p21 to Inhibit Cyclin-dependent Kinase-2 Activity and Induces Growth Arrest Independent of DNA Binding. J. Biol. Chem. 276: 29200-29209 [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»