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 Timchenko, N. A.
Right arrow Articles by Darlington, G. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Timchenko, N. A.
Right arrow Articles by Darlington, G. J.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, April 1999, p. 2936-2945, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

C/EBPalpha Regulates Formation of S-Phase-Specific E2F-p107 Complexes in Livers of Newborn Mice

Nikolai A. Timchenko,* Margie Wilde, and Gretchen J. Darlington

Department of Pathology, Baylor College of Medicine, Houston, Texas 77030

Received 24 September 1998/Returned for modification 9 November 1998/Accepted 21 January 1999

We previously showed that the rate of hepatocyte proliferation in livers from newborn C/EBPalpha knockout mice was increased. An examination of cell cycle-related proteins showed that the cyclin-dependent kinase (CDK) inhibitor p21 level was reduced in the knockout animals compared to that in wild-type littermates. Here we show additional cell cycle-associated proteins that are affected by C/EBPalpha . We have observed that C/EBPalpha controls the composition of E2F complexes through interaction with the retinoblastoma (Rb)-like protein, p107, during prenatal liver development. S-phase-specific E2F complexes containing E2F, DP, cdk2, cyclin A, and p107 are observed in the developing liver. In wild-type animals these complexes disappear by day 18 of gestation and are no longer present in the newborn animals. In the C/EBPalpha mutant, the S-phase-specific complexes do not diminish and persist to birth. The elevation of levels of the S-phase-specific E2F-p107 complexes in C/EBPalpha knockout mice correlates with the increased expression of several E2F-dependent genes such as those that encode cyclin A, proliferating cell nuclear antigen, and p107. The C/EBPalpha -mediated regulation of E2F binding is specific, since the deletion of another C/EBP family member, C/EBPbeta , does not change the pattern of E2F binding during prenatal liver development. The addition of bacterially expressed, purified His-C/EBPalpha to the E2F binding reaction resulted in the disruption of E2F complexes containing p107 in nuclear extracts from C/EBPalpha knockout mouse livers. Ectopic expression of C/EBPalpha in cultured cells also leads to a reduction of E2F complexes containing Rb family proteins. Coimmunoprecipitation analyses revealed an interaction of C/EBPalpha with p107 but none with cdk2, E2F1, or cyclin A. A region of C/EBPalpha that has sequence similarity to E2F is sufficient for the disruption of the E2F-p107 complexes. Despite its role as a DNA binding protein, C/EBPalpha brings about a change in E2F complex composition through a protein-protein interaction. The disruption of E2F-p107 complexes correlates with C/EBPalpha -mediated growth arrest of hepatocytes in newborn animals.

* Corresponding author. Mailing address: Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 770-2206. Fax: (713) 770-1032. E-mail: nikolait{at}bcm.tmc.edu.

Molecular and Cellular Biology, April 1999, p. 2936-2945, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Zhou, S., Si, J., Liu, T., DeWille, J. W. (2008). PIASy Represses CCAAT/Enhancer-binding Protein {delta} (C/EBP{delta}) Transcriptional Activity by Sequestering C/EBP{delta} to the Nuclear Periphery. J. Biol. Chem. 283: 20137-20148 [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]  
  • Harrison-Findik, D. D., Schafer, D., Klein, E., Timchenko, N. A., Kulaksiz, H., Clemens, D., Fein, E., Andriopoulos, B., Pantopoulos, K., Gollan, J. (2006). Alcohol Metabolism-mediated Oxidative Stress Down-regulates Hepcidin Transcription and Leads to Increased Duodenal Iron Transporter Expression. J. Biol. Chem. 281: 22974-22982 [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]  
  • 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]  
  • Yin, H., Glass, J. (2006). In Prostate Cancer Cells the Interaction of C/EBP{alpha} with Ku70, Ku80, and Poly(ADP-ribose) Polymerase-1 Increases Sensitivity to DNA Damage. J. Biol. Chem. 281: 11496-11505 [Abstract] [Full Text]  
  • Wang, G.-L., Shi, X., Salisbury, E., Sun, Y., Albrecht, J. H., Smith, R. G., Timchenko, N. A. (2006). Cyclin D3 Maintains Growth-Inhibitory Activity of C/EBP{alpha} by Stabilizing C/EBP{alpha}-cdk2 and C/EBP{alpha}-Brm Complexes.. Mol. Cell. Biol. 26: 2570-2582 [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]  
  • 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]  
  • 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]  
  • Chin, K.-T., Zhou, H.-J., Wong, C.-M., Lee, J. M.-F., Chan, C.-P., Qiang, B.-Q., Yuan, J.-G., Ng, I. O.-l., Jin, D.-Y. (2005). The liver-enriched transcription factor CREB-H is a growth suppressor protein underexpressed in hepatocellular carcinoma. Nucleic Acids Res 33: 1859-1873 [Abstract] [Full Text]  
  • Wang, G.-L., Timchenko, N. A. (2005). Dephosphorylated C/EBP{alpha} Accelerates Cell Proliferation through Sequestering Retinoblastoma Protein. Mol. Cell. Biol. 25: 1325-1338 [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]  
  • Tominaga, K., Magee, D. M., Matzuk, M. M., Pereira-Smith, O. M. (2004). PAM14, a Novel MRG- and Rb-Associated Protein, Is Not Required for Development and T-Cell Function in Mice. Mol. Cell. Biol. 24: 8366-8373 [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]  
  • Wang, G.-L., Iakova, P., Wilde, M., Awad, S., Timchenko, N. A. (2004). Liver tumors escape negative control of proliferation via PI3K/Akt-mediated block of C/EBP{alpha} growth inhibitory activity. Genes Dev. 18: 912-925 [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]  
  • 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]  
  • Dimova, D. K., Stevaux, O., Frolov, M. V., Dyson, N. J. (2003). Cell cycle-dependent and cell cycle-independent control of transcription by the Drosophila E2F/RB pathway. Genes Dev. 17: 2308-2320 [Abstract] [Full Text]  
  • Shim, M., Smart, R. C. (2003). Lithium Stabilizes the CCAAT/Enhancer-binding Protein {alpha} (C/EBP{alpha}) through a Glycogen Synthase Kinase 3 (GSK3)-independent Pathway Involving Direct Inhibition of Proteasomal Activity. J. Biol. Chem. 278: 19674-19681 [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]  
  • Welm, A. L., Timchenko, N. A., Ono, Y., Sorimachi, H., Radomska, H. S., Tenen, D. G., Lekstrom-Himes, J., Darlington, G. J. (2002). C/EBPalpha Is Required for Proteolytic Cleavage of Cyclin A by Calpain 3 in Myeloid Precursor Cells. J. Biol. Chem. 277: 33848-33856 [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]  
  • 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]  
  • 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]  
  • 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]  
  • Park, J.-S., Qiao, L., Gilfor, D., Yang, M. Y., Hylemon, P. B., Benz, C., Darlington, G., Firestone, G., Fisher, P. B., Dent, P. (2000). A Role for Both Ets and C/EBP Transcription Factors and mRNA Stabilization in the MAPK-dependent Increase in p21 Cip-1/WAF1/mda6 Protein Levels in Primary Hepatocytes. Mol. Biol. Cell 11: 2915-2932 [Abstract] [Full Text]  
  • Slomiany, B. A., D'Arigo, K. L., Kelly, M. M., Kurtz, D. T. (2000). C/EBPalpha Inhibits Cell Growth via Direct Repression of E2F-DP-Mediated Transcription. Mol. Cell. Biol. 20: 5986-5997 [Abstract] [Full Text]  
  • Zhu, S., Oh, H.-S., Shim, M., Sterneck, E., Johnson, P. F., Smart, R. C. (1999). C/EBPbeta Modulates the Early Events of Keratinocyte Differentiation Involving Growth Arrest and Keratin 1 and Keratin 10 Expression. Mol. Cell. Biol. 19: 7181-7190 [Abstract] [Full Text]  
  • Pan, Z., Hetherington, C. J., Zhang, D.-E. (1999). CCAAT/Enhancer-binding Protein Activates the CD14 Promoter and Mediates Transforming Growth Factor beta Signaling in Monocyte Development. J. Biol. Chem. 274: 23242-23248 [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]  
  • Allen-Jennings, A. E., Hartman, M. G., Kociba, G. J., Hai, T. (2001). The Roles of ATF3 in Glucose Homeostasis. A TRANSGENIC MOUSE MODEL WITH LIVER DYSFUNCTION AND DEFECTS IN ENDOCRINE PANCREAS. J. Biol. Chem. 276: 29507-29514 [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»