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(Received for publication, January 19, 1996, and in revised form, July 3, 1996)
From the CCAAT/enhancer binding protein
Volume 271, Number 40,
Issue of October 4, 1996
pp. 24753-24760
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
and§
Karolinska Institute, Department of
Biosciences at Novum S-141 57 Huddinge, Sweden and the
§ National Center for Human Genome Research, CGTB, National
Institutes of Health, Bethesda, Maryland 20892-1852
(C/EBP) is
a transcription factor that has been implicated in the regulation of
cell-specific gene expression mainly in hepatocytes and adipocytes but
also in several other terminally differentiated cells. It has been
previously demonstrated that the C/EBP protein is functionally
indispensable, as inactivation of the C/EBP gene by homologous
recombination in mice results in the death of animals homozygous for
the mutation shortly after birth (Wang, N., Finegold, M. J., Bradley,
A., Ou, C. N., Abdelsayed, S. V., Wilde, M. D., Taylor, L. R., Wilson,
D. R., and Darlington, G. J. (1995) Science 269, 1108-1112). Here we show that C/EBP 
1mice have defects in the
control of hepatic growth and lung development. The liver architecture
is disturbed, with acinar formation, in a pattern suggestive of either
regenerating liver or pseudoglandular hepatocellular carcinoma.
Pulmonary histology shows hyperproliferation of type II pneumocytes and
disturbed alveolar architecture. At the molecular level, accumulation
of glycogen and lipids in the liver and adipose tissues is impaired,
and the mutant animals are severely hypoglycemic. Levels of
c-myc and c-jun RNA are specifically induced by
several fold in the livers of the C/EBP / animals, indicating an
active proliferative stage. Furthermore, immunohistologic detection
with an antibody to proliferating cell nuclear antigen/cyclin shows a
5-10 times higher frequency of positively stained hepatocytes in
C/EBP / liver. These results suggest a critical role for
C/EBP in vivo for the acquisition of terminally
differentiated functions in liver including the maintenance of
physiologic energy homeostasis.
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A. F. Gombart, M. Shiohara, S. H. Kwok, K. Agematsu, A. Komiyama, and H. P. Koeffler Neutrophil-specific granule deficiency: homozygous recessive inheritance of a frameshift mutation in the gene encoding transcription factor CCAAT/enhancer binding protein-{epsilon} Blood, May 1, 2001; 97(9): 2561 - 2567. [Abstract] [Full Text] [PDF]
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S. E. Lyons, B. C. Shue, A. C. Oates, L. I. Zon, and P. P. Liu A novel myeloid-restricted zebrafish CCAAT/enhancer-binding protein with a potent transcriptional activation domain Blood, May 1, 2001; 97(9): 2611 - 2617. [Abstract] [Full Text] [PDF]
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 J. A. Lekstrom-Himes The Role of C/EBP{{varepsilon}} in the Terminal Stages of Granulocyte Differentiation Stem Cells, February 1, 2001; 19(2): 125 - 133. [Abstract] [Full Text]
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 F. T. Kockar, P. Foka, T. R. Hughes, S. Kousteni, and D. P. Ramji Analysis of the Xenopus laevis CCAAT-enhancer binding protein {{alpha}} gene promoter demonstrates species-specific differences in the mechanisms for both auto-activation and regulation by Sp1 Nucleic Acids Res., January 15, 2001; 29(2): 362 - 372. [Abstract] [Full Text] [PDF]
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A. Menendez-Hurtado, A. Santos, and A. Perez-Castillo Characterization of the Promoter Region of the Rat CCAAT/Enhancer-Binding Protein {alpha} Gene and Regulation by Thyroid Hormone in Rat Immortalized Brown Adipocytes Endocrinology, November 1, 2000; 141(11): 4164 - 4170. [Abstract] [Full Text] [PDF]
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A. Heydemann, S. Warming, C. Clendenin, K. Sigrist, J. P. Hjorth, and M. C. Simon A minimal c-fes cassette directs myeloid-specific expression in transgenic mice Blood, November 1, 2000; 96(9): 3040 - 3048. [Abstract] [Full Text] [PDF]
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 C. F. Calkhoven, C. Müller, and A. Leutz Translational control of C/EBPalpha and C/EBPbeta isoform expression Genes & Dev., August 1, 2000; 14(15): 1920 - 1932. [Abstract] [Full Text]
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E. D. Rosen, C. J. Walkey, P. Puigserver, and B. M. Spiegelman Transcriptional regulation of adipogenesis Genes & Dev., June 1, 2000; 14(11): 1293 - 1307. [Full Text]
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Y. L. Zhou and M. L. Snead Identification of CCAAT/Enhancer-binding Protein alpha as a Transactivator of the Mouse Amelogenin Gene J. Biol. Chem., April 14, 2000; 275(16): 12273 - 12280. [Abstract] [Full Text] [PDF]
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T. N. Cassel, L. Nordlund-Möller, O. Andersson, J.-A. Gustafsson, and M. Nord C/EBPalpha and C/EBPdelta Activate the Clara Cell Secretory Protein Gene through Interaction with Two Adjacent C/EBP-Binding Sites Am. J. Respir. Cell Mol. Biol., April 1, 2000; 22(4): 469 - 480. [Abstract] [Full Text]
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 T. Kaisho, H. Tsutsui, T. Tanaka, T. Tsujimura, K. Takeda, T. Kawai, N. Yoshida, K. Nakanishi, and S. Akira Impairment of Natural Killer Cytotoxic Activity and Interferon {gamma} Production in CCAAT/Enhancer Binding Protein {gamma}-deficient Mice J. Exp. Med., December 6, 1999; 190(11): 1573 - 1582. [Abstract] [Full Text] [PDF]
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J. P. O'Rourke, G. C. Newbound, J. A. Hutt, and J. DeWille CCAAT/Enhancer-binding Protein delta Regulates Mammary Epithelial Cell G0 Growth Arrest and Apoptosis J. Biol. Chem., June 4, 1999; 274(23): 16582 - 16589. [Abstract] [Full Text] [PDF]
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C. Arizmendi, S. Liu, C. Croniger, V. Poli, and J. E. Friedman The Transcription Factor CCAAT/Enhancer-binding Protein beta Regulates Gluconeogenesis and Phosphoenolpyruvate Carboxykinase (GTP) Gene Transcription during Diabetes J. Biol. Chem., May 7, 1999; 274(19): 13033 - 13040. [Abstract] [Full Text] [PDF]
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J. Lekstrom-Himes and K. G. Xanthopoulos CCAAT/Enhancer Binding Protein varepsilon Is Critical for Effective Neutrophil-Mediated Response to Inflammatory Challenge Blood, May 1, 1999; 93(9): 3096 - 3105. [Abstract] [Full Text] [PDF]
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N. A. Timchenko, M. Wilde, and G. J. Darlington C/EBPalpha Regulates Formation of S-Phase-Specific E2F-p107 Complexes in Livers of Newborn Mice Mol. Cell. Biol., April 1, 1999; 19(4): 2936 - 2945. [Abstract] [Full Text] [PDF]
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K. H. Kaestner, J. Katz, Y. Liu, D. J. Drucker, and G. Schütz Inactivation of the winged helix transcription factor HNF3alpha affects glucose homeostasis and islet glucagon gene expression in vivo Genes & Dev., February 15, 1999; 13(4): 495 - 504. [Abstract] [Full Text]
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C. Croniger, P. Leahy, L. Reshef, and R. W. Hanson C/EBP and the Control of Phosphoenolpyruvate Carboxykinase Gene Transcription in the Liver J. Biol. Chem., November 27, 1998; 273(48): 31629 - 31632. [Full Text] [PDF]
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A. M. Diehl Roles of CCAAT/Enhancer-binding Proteins in Regulation of Liver Regenerative Growth J. Biol. Chem., November 20, 1998; 273(47): 30843 - 30846. [Abstract] [Full Text] [PDF]
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G. J. Darlington, S. E. Ross, and O. A. MacDougald The Role of C/EBP Genes in Adipocyte Differentiation J. Biol. Chem., November 13, 1998; 273(46): 30057 - 30060. [Full Text] [PDF]
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V. M. Christoffels, T. Grange, K. H. Kaestner, T. J. Cole, G. J. Darlington, C. M. Croniger, and W. H. Lamers Glucocorticoid Receptor, C/EBP, HNF3, and Protein Kinase A Coordinately Activate the Glucocorticoid Response Unit of the Carbamoylphosphate Synthetase I Gene Mol. Cell. Biol., November 1, 1998; 18(11): 6305 - 6315. [Abstract] [Full Text]
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J. Lekstrom-Himes and K. G. Xanthopoulos Biological Role of the CCAAT/Enhancer-binding Protein Family of Transcription Factors J. Biol. Chem., October 30, 1998; 273(44): 28545 - 28548. [Abstract] [Full Text] [PDF]
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T. Kimura, V. M. Christoffels, S. Chowdhury, K. Iwase, H. Matsuzaki, M. Mori, W. H. Lamers, G. J. Darlington, and M. Takiguchi Hypoglycemia-associated Hyperammonemia Caused by Impaired Expression of Ornithine Cycle Enzyme Genes in C/EBPalpha Knockout Mice J. Biol. Chem., October 16, 1998; 273(42): 27505 - 27510. [Abstract] [Full Text] [PDF]
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P. Zhang, A. Iwama, M. W. Datta, G. J. Darlington, D. C. Link, and D. G. Tenen Upregulation of Interleukin 6 and Granulocyte Colony-Stimulating Factor Receptors by Transcription Factor CCAAT Enhancer Binding Protein alpha (C/EBPalpha ) Is Critical for Granulopoiesis J. Exp. Med., September 21, 1998; 188(6): 1173 - 1184. [Abstract] [Full Text] [PDF]
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M. S. Petrovick, S. W. Hiebert, A. D. Friedman, C. J. Hetherington, D. G. Tenen, and D.-E. Zhang Multiple Functional Domains of AML1: PU.1 and C/EBPalpha Synergize with Different Regions of AML1 Mol. Cell. Biol., July 1, 1998; 18(7): 3915 - 3925. [Abstract] [Full Text]
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H. S. Radomska, C. S. Huettner, P. Zhang, T. Cheng, D. T. Scadden, and D. G. Tenen CCAAT/Enhancer Binding Protein alpha Is a Regulatory Switch Sufficient for Induction of Granulocytic Development from Bipotential Myeloid Progenitors Mol. Cell. Biol., July 1, 1998; 18(7): 4301 - 4314. [Abstract] [Full Text]
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H. H. Cha, E. J. Cram, E. C. Wang, A. J. Huang, H. G. Kasler, and G. L. Firestone Glucocorticoids Stimulate p21 Gene Expression by Targeting Multiple Transcriptional Elements within a Steroid Responsive Region of the p21waf1/cip1 Promoter in Rat Hepatoma Cells J. Biol. Chem., January 23, 1998; 273(4): 1998 - 2007. [Abstract] [Full Text] [PDF]
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E. J. Cram, R. A. Ramos, E. C. Wang, H. H. Cha, Y. Nishio, and G. L. Firestone Role of the CCAAT/Enhancer Binding Protein-alpha Transcription Factor in the Glucocorticoid Stimulation of p21waf1/cip1 Gene Promoter Activity in Growth-arrested Rat Hepatoma Cells J. Biol. Chem., January 23, 1998; 273(4): 2008 - 2014. [Abstract] [Full Text] [PDF]
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D. R. Breed, L. R. Margraf, J. L. Alcorn, and C. R. Mendelson Transcription Factor C/EBP{delta} in Fetal Lung: Developmental Regulation and Effects of Cyclic Adenosine 3',5'-Monophosphate and Glucocorticoids Endocrinology, December 1, 1997; 138(12): 5527 - 5534. [Abstract] [Full Text] [PDF]
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D. G. Tenen, R. Hromas, J. D. Licht, and D.-E. Zhang Transcription Factors, Normal Myeloid Development, and Leukemia Blood, July 15, 1997; 90(2): 489 - 519. [Full Text] [PDF]
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W.-H. Zhang, R. Srihari, R. N. Day, and F. Schaufele CCAAT/Enhancer-binding Protein alpha Alters Histone H3 Acetylation at Large Subnuclear Domains J. Biol. Chem., October 26, 2001; 276(44): 40373 - 40376. [Abstract] [Full Text] [PDF]
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Y. L. Zhou, Y. Lei, and M. L. Snead Functional Antagonism between Msx2 and CCAAT/Enhancer-binding Protein alpha in Regulating the Mouse Amelogenin Gene Expression Is Mediated by Protein-Protein Interaction J. Biol. Chem., September 8, 2000; 275(37): 29066 - 29075. [Abstract] [Full Text] [PDF]
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C. M. Croniger, C. Millward, J. Yang, Y. Kawai, I. J. Arinze, S. Liu, M. Harada-Shiba, K. Chakravarty, J. E. Friedman, V. Poli, et al. Mice with a Deletion in the Gene for CCAAT/Enhancer-binding Protein beta Have an Attenuated Response to cAMP and Impaired Carbohydrate Metabolism J. Biol. Chem., January 5, 2001; 276(1): 629 - 638. [Abstract] [Full Text] [PDF]
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H. G. Linhart, K. Ishimura-Oka, F. DeMayo, T. Kibe, D. Repka, B. Poindexter, R. J. Bick, and G. J. Darlington C/EBPalpha is required for differentiation of white, but not brown, adipose tissue PNAS, October 23, 2001; 98(22): 12532 - 12537. [Abstract] [Full Text] [PDF]
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