* 189965

CCAAT/ENHANCER-BINDING PROTEIN, BETA; CEBPB


Alternative titles; symbols

C/EBP-BETA
INTERLEUKIN 6-DEPENDENT DNA-BINDING PROTEIN; IL6DBP
LIVER ACTIVATOR PROTEIN; LAP
LIVER-ENRICHED TRANSCRIPTIONAL ACTIVATOR PROTEIN
TRANSCRIPTION FACTOR 5; TCF5
NFIL6


HGNC Approved Gene Symbol: CEBPB

Cytogenetic location: 20q13.13     Genomic coordinates (GRCh38): 20:50,190,583-50,192,690 (from NCBI)


TEXT

Cloning and Expression

Interleukin-6 (147620), an important polypeptide hormone produced by various cell types, plays a central role in a variety of biologic phenomena. It modulates the immune response, is involved in the control of body temperature, and in the liver regulates the synthesis of plasma proteins, the 'acute phase' proteins. The IL6 receptor (IL6R; 147880) consists of 2 chains, a ligand-binding chain and a glycoprotein essential for transmembrane signaling which associates with the ligand-binding chain only after binding of the ligand. Two different IL6-responsive elements involved in the induction of acute phase proteins (IL6REs) were identified, one in the promoter of the haptoglobin and hemopexin genes and another in the promoter of the alpha-2 macroglobulin gene. The haptoglobin and hemopexin gene IL6RE sequence contains the recognition site for a family of nuclear proteins. One of these proteins, IL6-dependent DNA-binding protein (IL6DBP), is induced by IL6. It is identical to the liver-enriched transcriptional activator protein of Descombes et al. (1990). This protein was found to have a molecular weight of 32 kD and to stimulate transcription of chimeric genes containing the albumin D-promoter elements both in vivo and in vitro. LAP shared extensive sequence homology (71%) in its DNA-binding and leucine zipper domains with CCAAT/enhancer-binding protein (CEBPA; 116897). As a consequence, these 2 proteins show an indistinguishable DNA-binding specificity and readily heterodimerize. TCF5 is also identical to NF-IL6 (Akira et al., 1990). CEBPA and NF-IL6 (CEBPB, according to the nomenclature proposed by Cao et al., 1991) are 2 transcription factors belonging to a family of DNA-binding proteins predominantly characterized by a leucine zipper motif that mediates dimerization and a basic DNA binding domain. Notably, the CEBPA and CEBPB genes contain no introns.


Biochemical Features

Although collagen is known to enhance hepatocyte differentiation and hepatocytes produce collagen in vivo, the transcription factors responsible for collagen type I gene expression in hepatic cells is not known. Houglum et al. (1994) showed that LAP binds to the COL1A1 (120150) promoter at both reverse CCAAT motifs and activates transcription. Furthermore, they found an upstream element, collagen element I (-370/-344), which shares homology with the LAP binding cis-element of the albumin promoter (9 of 13 bp). This collagen element I stimulates transcription in both orientations and when placed in front of either a homologous or a heterologous chimeric report construct. Thus, LAP may be important in the expression of collagen and differentiated hepatocytes through both the promoter and the newly described upstream element.

Hormonal induction of growth-arrested 3T3-L1 preadipocytes rapidly activates expression of CEBPB. Acquisition of DNA-binding activity by CEBPB, however, is delayed until the cells synchronously enter the S phase of mitotic clonal expansion (MCE). After MCE, CEBPB activates expression of CEBPA and peroxisome proliferator-activated receptor gamma (PPARG; 601487), which then transcriptionally activate genes that give rise to the adipocyte phenotype. Zhang et al. (2004) studied the effect on adipogenesis of the CEBPB dominant-negative mutation that blocks CEBPB DNA binding by dimerizing with its leucine zipper. They provided evidence that the dominant-negative mutant prevented entry of CEBPB into the nucleus of 3T3-L1 preadipocytes and thereby blocks MCE and adipogenesis.


Gene Function

Menard et al. (2002) showed that Cebpb was expressed in mouse cortical progenitor cells and could induce expression of a reporter gene containing the minimal promoter of alpha-tubulin (TUBA1A; 602529), a neuron-specific gene. Gel and supershift assays confirmed that Cebpb bound the alpha-tubulin promoter in embryonic mouse brain. Menard et al. (2002) also showed that Cebpb was a downstream target of Mek (see 176872), which activated Rsk (see 601684) to phosphorylate Cebpb.

By computational analysis of the expression patterns of thousands of genes across hundreds of tumor specimens, Lamb et al. (2003) found that CEBP-beta participates in the consequences of cyclin D1 (CCND1; 168461) overexpression. Functional analysis confirmed the involvement of CEBPB in the regulation of genes affected by cyclin D1 and established CEBPB as a principal effector of cyclin D1 activity in human cancer.

By expression profiling of ALK (105590)-positive anaplastic large cell lymphomas (ALCLs), Piva et al. (2006) identified a large group of ALK-regulated genes. Functional RNA interference screening on a set of these transcriptional targets revealed that CEBPB and BCL2A1 (601056) were absolutely necessary to induce cell transformation and/or to sustain growth and survival of ALK-positive ALCL cells.

Dudaronek et al. (2007) showed that Ifnb (147720) induced expression of Lip, a truncated, dominant-negative isoform of Cebpb, and suppressed active simian immunodeficiency virus (SIV) replication in macaque macrophages. In a human monocyte cell line, IFNB induced phosphorylation of CUGBP1 (601074) and formation of CUGBP1-CEBPB mRNA complexes. Depletion of Cugbp1 in macaque macrophages via small interfering RNA showed that Cugbp1 was required for Ifnb-mediated induction of Lip and for Ifnb-mediated suppression of SIV replication. Dudaronek et al. (2007) concluded that CUGBP1 is a downstream effector of IFNB signaling in primary macrophages that plays an important role in innate immune responses controlling acute human immunodeficiency virus (HIV) or SIV replication in brain.

Using a cDNA complementation screen, Kinoshita and Taguchi (2008) identified NFIL6 as a host molecule that rendered primary CD4 (186940)-positive T cells permissive for HIV-1 replication. They found that NFIL6 regulated HIV-1 replication during reverse transcription after infection by binding to and inactivating the cytidine deaminase activity of APOBEC3G (607113) and also during gene transcription after integration. Binding and inactivation of APOBEC3G required ser288 in NFIL6. Overexpression of NFIL6 in nonpermissive cells enhanced HIV-1 replication, even in the absence of the HIV-1 protein Vif. Kinoshita and Taguchi (2008) proposed that NFIL6 evolved to negatively regulate APOBEC3G to limit DNA mutations, but that this mechanism backfires during HIV-1 infection, where it facilitates viral reverse transcription and replication.

Ishikawa et al. (2008) demonstrated that cAMP-induced binding of CEBP-beta to multiple motifs in the CYP19A1 (107910) promoter I.3/II region is a critical mechanism regulating aromatase expression in leiomyoma (see 150699) smooth muscle cells in primary culture. The authors concluded that definition of this mechanism further may assist in designing inhibitors of aromatase specific for leiomyoma tissue.

Kajimura et al. (2009) demonstrated that PRDM16 (605557) forms a transcriptional complex with the active form of C/EBP-beta, acting as a critical molecular unit that controls the cell fate switch from myoblastic precursors to brown fat cells. Forced expression of PRDM16 and C/CEBP-beta was sufficient to induce a fully functional brown fat program in naive fibroblastic cells, including skin fibroblasts from mouse and man. Transplantation of fibroblasts expressing these 2 factors into mice gave rise to an ectopic fat pad with the morphologic and biochemical characteristics of brown fat. Like endogenous brown fat, this synthetic brown fat tissue acted as a sink for glucose uptake, as determined by positron emission tomography with fluorodeoxyglucose. Kajimura et al. (2009) concluded that the PRMD16-C/EBP-beta complex initiates brown fat formation from myoblastic precursors and may provide opportunities for the development of therapeutics for obesity and type 2 diabetes.

Carro et al. (2010) used reverse engineering and an unbiased interrogation of a glioma-specific regulatory network to reveal the transcriptional module that activates expression of mesenchymal genes in malignant glioma. Two transcription factors, C/EBP-beta and STAT3 (102582), emerged as synergistic initiators and master regulators of mesenchymal transformation. Ectopic coexpression of C/EBP-beta and STAT3 reprogrammed neural stem cells along the aberrant mesenchymal lineage, whereas elimination of the 2 factors in glioma cells led to collapse of the mesenchymal signature and reduced tumor aggressiveness. In human glioma, expression of C/EBP-beta and STAT3 correlated with mesenchymal differentiation and predicted poor clinical outcome. Carro et al. (2010) concluded that the activation of a small regulatory module is necessary and sufficient to initiate and maintain an aberrant phenotypic state in cancer cells.

Bostrom et al. (2010) found that expression of Cebpb in mice was significantly downregulated during cardiac hypertrophy induced by exercise endurance training, but not during pathologic cardiac hypertrophy. Knockdown of Cebpb by small interfering RNA in primary rat cardiomyocytes increased cell size, the rate of protein synthesis, and cell number. Coimmunoprecipitation analysis showed that Cebpb interacted with Srf (600589), and knockdown of Cebpb increased binding of Srf to the promoters of the critical cardiac genes alpha-MHC (MYH6; 160710) and Gata4 (600576). Expression of Cited4 (606815) increased robustly in exercised hearts, and its expression level was altered by Cebpb gain or loss of function in vitro. Knockdown of Cited4 completely abolished the effect of Cebpb reduction on cardiomyocyte proliferation.

Overexpression of P-cadherin (CDH3; 114021) has been associated with proliferative lesions of high histologic grade, decreased cell polarity, and poor survival of patients with breast cancer. In vitro studies showed that it can be upregulated by the antiestrogen drug ICI 182,780, suggesting that the lack of estrogen receptor-alpha (ESRA; 133430) signaling may responsible for the aberrant P-cadherin overexpression and for its role in inducing breast cancer cell invasion and migration. Albergaria et al. (2010) showed that ICI 182,780 was able to increase P-cadherin promoter activity, inducing high levels of the active chromatin marker H3 lysine-4 dimethylation (H3K4me2). Albergaria et al. (2010) also showed that CEBPB was able to upregulate P-cadherin promoter activity in breast cancer cells. Moreover, the expression of P-cadherin and CEBPB were highly associated in human breast carcinomas and linked with a worse prognosis in breast cancer patients. The authors concluded that epigenetic upregulation of P-cadherin by ICI 182,780 in MCF-7/AZ breast cancer cells occurs through chromatin remodeling at the CDH3 promoter, bringing forward the growing evidence that ESRA signaling abrogation by antiestrogens may be able to induce the expression of ESRA-repressed genes which, in the appropriate cell biology context, may contribute to a breast cancer cell invasion phenotype.


Mapping

By analysis of human/mouse somatic cell hybrids, Szpirer et al. (1991) assigned the TCF5 gene to human chromosome 20. By corresponding studies in rat/mouse hybrids, they localized the gene to rat chromosome 3. Hendricks-Taylor et al. (1992) mapped the human CEBPB gene to chromosome 20 by Southern blot analysis of Chinese hamster/human and mouse/human somatic cell hybrids and regionalized the gene to 20q13.1 by fluorescence in situ hybridization. Using interspecific backcross analysis, Jenkins et al. (1995) showed that the Cebpb gene maps to mouse chromosome 2.


Evolution

Lynch et al. (2011) showed that amino acid changes in the transcription factor CEBPB in the stem lineage of placental mammals changed the way it responds to cAMP/protein kinase A (PKA; see 176911) signaling. By functionally analyzing resurrected ancestral proteins, they identified 3 amino acid substitutions in an internal regulatory domain of CEBPB that are responsible for the novel function. These amino acid substitutions reorganize the location of key phosphorylation sites, introducing a new site and removing 2 ancestral sites, reversing the response of CEBPB to GSK-3-beta (605004)-mediated phosphorylation from repression to activation. Lynch et al. (2011) concluded that changing the response of transcription factors to signaling pathways can be an important mechanism of gene regulatory evolution.


Animal Model

To determine the role of C/EBP-beta in the regenerating liver, Greenbaum et al. (1998) examined the regenerative response after partial hepatectomy in mice that had a targeted disruption of the gene. Posthepatectomy, hepatocyte DNA synthesis was decreased to 25% of normal in the homozygous deficient mice. The reduced regenerative response was associated with a prolonged period of hypoglycemia that was independent of expression of C/EBP-alpha protein and gluconeogenic genes. The homozygous C/EBP-beta-deficient livers showed reduced expression of immediate-early growth-control genes. This study demonstrated that C/EBP is required for a normal proliferative response.

Wang et al. (2000) performed detailed biochemical experiments on CEBPB-deficient mice. They found that the deletion caused decreased plasma free fatty acid levels and increased insulin signal transduction, specifically in skeletal muscle, and that both contribute to increased whole-body insulin sensitivity.

Croniger et al. (2001) noted that there are 2 distinct phenotypes, A and B, in Cebpb-deficient mice. Phenotype A mice survive to adulthood but have hypoglycemia as well as lipid, amino acid, and immunologic deficiencies. Phenotype B mice survive only 2 hours after birth and display profound hypoglycemia in spite of above normal levels of hepatic glycogen. Croniger et al. (2001) detailed the metabolic consequences in Cebpb-deficient mice. In these mice, relatively small changes in the rate of hepatic cAMP degradation and a shift in the pattern of protein kinase A (PKA; see 176911) isoform gene expression result in a lower concentration of cAMP in the liver. More cAMP is required to activate PKA, and the result is a failure of the normal response to glucagon.

Upon activation by liver injury, hepatic stellate cells produce excessive fibrous tissue leading to cirrhosis. Buck et al. (2001) found that the hepatotoxin CCl4 induced activation of Rsk (601684), phosphorylation of Cebpb on thr217 (Cebpb-Pthr217), and proliferation of stellate cells in normal mice, but it caused apoptosis of these cells in Cebpb -/- or Cebpb-ala217 (a dominant-negative nonphosphorylatable mutant) transgenic mice. Both Cebpb-Pthr217 and the phosphorylation mimicked Cebpb-glu217, but not Cebpb-ala217; were associated with procaspase-1 (147678) and -8 (601763) in vivo and in vitro; and inhibited activation of these procaspases. These data suggested that Cebpb phosphorylation on thr217 creates a functional XEXD caspase substrate/inhibitor box (K-phospho-T(217)VD) that is mimicked by Cebpb-glu217 (KE(217)VD). Cebpb -/- and Cebpb-ala217 stellate cells were rescued from apoptosis by the cell-permeant KE(217)VD tetrapeptide or Cebpb-glu217.

A surge of luteinizing hormone (LH; see 152780) from the pituitary gland triggers ovulation, oocyte maturation, and luteinization for successful reproduction in mammals. Because the signaling molecules RAS (190020) and ERK1/2 (see 601795) are activated by an LH surge in granulosa cells of preovulatory follicles, Fan et al. (2009) disrupted Erk1/2 in mouse granulosa cells and provided in vivo evidence that these kinases are necessary for LH-induced oocyte resumption of meiosis, ovulation, and luteinization. In addition, biochemical analyses and selected disruption of the Cebpb gene in granulosa cells demonstrated that C/EBP-beta is a critical downstream mediator of ERK1/2 activation. Thus, Fan et al. (2009) concluded that ERK1/2 and C/EBP-beta constitute an in vivo LH-regulated signaling pathway that controls ovulation- and luteinization-related events.

Bostrom et al. (2010) stated that homozygous Cebpb deletion in mice results in pre- and perinatal lethality, but that Cebpb +/- mice are relatively normal. They found increased heart weight and cardiomyocyte hypertrophy in Cebpb +/- mice, similar to that found in wildtype mice following endurance training. Cebpb +/- mice displayed a clear increase in exercise capacity at baseline, but no hypertrophy following training. Cultured cardiomyocytes from Cebpb +/- mice proliferated more readily than wildtype cardiomyocytes. Cebpb +/- mice also showed resistance to pathologic cardiac hypertrophy and dysfunction caused by pressure overload. Knockdown of Cebpb in zebrafish caused an increase in cardiomyocyte cell number, but no change in cardiomyocyte size. Bostrom et al. (2010) concluded that reduced CEBPB activity during exercise contributes to physiologic cardiac hypertrophy.


REFERENCES

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  2. Albergaria, A., Ribeiro, A. S., Pinho, S., Milanezi, F., Carneiro, V., Sousa, B., Sousa, S., Oliveira, C., Machado, J. C., Seruca, R., Paredes, J., Schmitt, F. ICI 182,780 induces P-cadherin overexpression in breast cancer cells through chromatin remodelling at the promoter level: a role for C/EBP beta in CDH3 gene activation. Hum. Molec. Genet. 19: 2554-2566, 2010. [PubMed: 20385540, related citations] [Full Text]

  3. Bostrom, P., Mann, N., Wu, J., Quintero, P. A., Plovie, E. R., Panakova, D., Gupta, R. K., Xiao, C., MacRae, C. A., Rosenzweig, A., Spiegelman, B. M. C/EBP-beta controls exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell 143: 1072-1083, 2010. [PubMed: 21183071, images, related citations] [Full Text]

  4. Buck, M., Poli, V., Hunter, T., Chojkier, M. C/EBP-beta phosphorylation by RSK creates a functional XEXD caspase inhibitory box critical for cell survival. Molec. Cell 8: 807-816, 2001. [PubMed: 11684016, related citations] [Full Text]

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  6. Carro, M. S., Lim, W. K., Alvarez, M. J., Bollo, R. J., Zhao, X., Snyder, E. Y., Sulman, E. P., Anne, S. L., Doetsch, F., Colman, H., Lasorella, A., Aldape, K., Califano, A., Iavarone, A. The transcriptional network for mesenchymal transformation of brain tumours. Nature 463: 318-325, 2010. [PubMed: 20032975, images, related citations] [Full Text]

  7. Croniger, C. M., Millward, C., Yang, J., Kawai, Y., Arinze, I. J., Liu, S., Harada-Shiba, M., Chakravarty, K., Friedman, J. E., Poli, V., Hanson, R. W. 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. 276: 629-638, 2001. [PubMed: 11024029, related citations] [Full Text]

  8. Descombes, P., Chojkier, M., Lichtsteiner, S., Falvey, E., Schibler, U. LAP, a novel member of the C/EBP gene family, encodes a liver-enriched transcriptional activator protein. Genes Dev. 4: 1541-1551, 1990. [PubMed: 2253878, related citations] [Full Text]

  9. Dudaronek, J. M., Barber, S. A., Clements, J. E. CUGBP1 is required for IFN-beta-mediated induction of dominant-negative CEBP-beta and suppression of SIV replication in macrophages. J. Immun. 179: 7262-7269, 2007. [PubMed: 18025168, related citations] [Full Text]

  10. Fan, H.-Y., Liu, Z., Shimada, M., Sterneck, E., Johnson, P. F., Hedrick, S. M., Richards, J. S. MAPK3/1 (ERK1/2) in ovarian granulosa cells are essential for female fertility. Science 324: 938-941, 2009. [PubMed: 19443782, images, related citations] [Full Text]

  11. Greenbaum, L. E., Li, W., Cressman, D. E., Peng, Y., Ciliberto, G., Poli, V., Taub, R. CCAAT enhancer-binding protein beta is required for normal hepatocyte proliferation in mice after partial hepatectomy. J. Clin. Invest. 102: 996-1007, 1998. [PubMed: 9727068, related citations] [Full Text]

  12. Hendricks-Taylor, L. R., Bachinski, L. L., Siciliano, M. J., Fertitta, A., Trask, B., de Jong, P. J., Ledbetter, D. H., Darlington, G. J. The CCAAT/enhancer binding protein (C/EBP-alpha) gene (CEBPA) maps to human chromosome 19q13.1 and the related nuclear factor NF-IL6 (C/EBP-beta) gene (CEBPB) maps to human chromosome 20q13.1. Genomics 14: 12-17, 1992. [PubMed: 1427819, related citations] [Full Text]

  13. Houglum, K., Buck, M., Adir, V., Chojkier, M. LAP (NF-IL6) transactivates the collagen alpha-1(I) gene from a 5-prime regulatory region. J. Clin. Invest. 94: 808-814, 1994. [PubMed: 8040336, related citations] [Full Text]

  14. Ishikawa, H., Fenkci, V., Marsh, E. E., Yin, P., Chen, D., Cheng, Y.-H., Reisterd, S., Lin, Z., Bulun, S. E. CCAAT/enhancer binding protein beta regulates aromatase expression via multiple and novel cis-regulatory sequences in uterine leiomyoma. J. Clin. Endocr. Metab. 93: 981-991, 2008. Note: Erratum: J. Clin. Endocr. Metab. 94: 1476 only, 2009. [PubMed: 18182446, images, related citations] [Full Text]

  15. Jenkins, N. A., Gilbert, D. J., Cho, B. C., Strobel, M. C., Williams, S. C., Copeland, N. G., Johnson, P. F. Mouse chromosomal location of the CCAAT/enhancer binding proteins C/EBP-beta (Cebpb), C/EBP-delta (Cebpd), and CRP1 (Cebpe). Genomics 28: 333-336, 1995. [PubMed: 8530045, related citations] [Full Text]

  16. Kajimura, S., Seale, P., Kubota, K., Lunsford, E., Frangioni, J. V., Gygi, S. P., Spiegelman, B. M. Initiation of myoblast to brown fat switch by a PRDM16/C/EBP-beta transcriptional complex. Nature 460: 1154-1158, 2009. [PubMed: 19641492, images, related citations] [Full Text]

  17. Kinoshita, S. M., Taguchi, S. NF-IL6 (C/EBP-beta) induces HIV-1 replication by inhibiting cytidine deaminase APOBEC3G. Proc. Nat. Acad. Sci. 105: 15022-15027, 2008. [PubMed: 18809921, images, related citations] [Full Text]

  18. Lamb, J., Ramaswamy, S., Ford, H. L., Contreras, B., Martinez, R. V., Kittrell, F. S., Zahnow, C. A., Patterson, N., Golub, T. R., Ewen, M. E. A mechanism of cyclin D1 action encoded in the patterns of gene expression in human cancer. Cell 114: 323-334, 2003. [PubMed: 12914697, related citations] [Full Text]

  19. Lynch, V. J., May, G., Wagner, G. P. Regulatory evolution through divergence of a phosphoswitch in the transcription factor CEBPB. Nature 480: 383-386, 2011. Note: Erratum: Nature 508: 420 only, 2014. [PubMed: 22080951, related citations] [Full Text]

  20. Menard, C., Hein, P., Paquin, A., Savelson, A., Yang, X. M., Lederfein, D., Barnabe-Heider, F., Mir, A. A., Sterneck, E., Peterson, A. C., Johnson, P. F., Vinson, C., Miller, F. D. An essential role for a MEK-C/EBP pathway during growth factor-regulated cortical neurogenesis. Neuron 36: 597-610, 2002. [PubMed: 12441050, related citations] [Full Text]

  21. Piva, R., Pellegrino, E., Mattioli, M., Agnelli, L., Lombardi, L., Boccalatte, F., Costa, G., Ruggeri, B. A., Cheng, M., Chiarle, R., Palestro, G., Neri, A., Inghirami, G. Functional validation of the anaplastic lymphoma kinase signature identifies CEBPB and BCL2A1 as critical target genes. J. Clin. Invest. 116: 3171-3182, 2006. [PubMed: 17111047, images, related citations] [Full Text]

  22. Szpirer, J., Szpirer, C., Riviere, M., Houart, C., Baumann, M., Fey, G. H., Poli, V., Cortese, R., Islam, M. Q., Levan, G. The interleukin-6-dependent DNA-binding protein gene (transcription factor 5: TCF5) maps to human chromosome 20 and rat chromosome 3, the IL6 receptor locus (IL6R) to human chromosome 1 and rat chromosome 2, and the rat IL6 gene to rat chromosome 4. Genomics 10: 539-546, 1991. [PubMed: 1889804, related citations] [Full Text]

  23. Wang, L., Shao, J., Muhlenkamp, P., Liu, S., Klepcyk, P., Ren, J., Friedman, J. E. Increased insulin receptor substrate-1 and enhanced skeletal muscle insulin sensitivity in mice lacking CCAAT/enhancer-binding protein beta. J. Biol. Chem. 275: 14173-14181, 2000. [PubMed: 10747954, related citations] [Full Text]

  24. Zhang, J.-W., Tang, Q.-Q., Vinson, C., Lane, M. D. Dominant-negative C/EBP disrupts mitotic clonal expansion and differentiation of 3T3-L1 preadipocytes. Proc. Nat. Acad. Sci. 101: 43-47, 2004. [PubMed: 14688407, images, related citations] [Full Text]


George E. Tiller - updated : 9/13/2013
Ada Hamosh - updated : 2/27/2012
Patricia A. Hartz - updated : 3/15/2011
Ada Hamosh - updated : 2/18/2010
Ada Hamosh - updated : 9/9/2009
Ada Hamosh - updated : 8/17/2009
John A. Phillips, III - updated : 4/23/2009
Paul J. Converse - updated : 3/24/2009
Paul J. Converse - updated : 12/18/2008
Ada Hamosh - updated : 10/28/2008
Patricia A. Hartz - updated : 1/25/2007
Patricia A. Hartz - updated : 5/8/2006
Victor A. McKusick - updated : 2/6/2004
Stylianos E. Antonarakis - updated : 11/13/2001
Paul J. Converse - updated : 3/15/2001
Ada Hamosh - updated : 8/14/2000
Victor A. McKusick - updated : 9/25/1998
Creation Date:
Victor A. McKusick : 10/26/1990
alopez : 04/25/2014
alopez : 9/13/2013
alopez : 1/30/2013
alopez : 3/2/2012
terry : 2/27/2012
mgross : 3/17/2011
terry : 3/15/2011
alopez : 2/22/2010
alopez : 2/22/2010
terry : 2/18/2010
alopez : 9/11/2009
terry : 9/9/2009
alopez : 8/21/2009
terry : 8/17/2009
alopez : 4/23/2009
mgross : 3/24/2009
terry : 3/24/2009
mgross : 12/18/2008
mgross : 12/5/2008
terry : 10/28/2008
mgross : 1/25/2007
mgross : 6/6/2006
terry : 5/8/2006
cwells : 2/10/2004
terry : 2/6/2004
mgross : 11/13/2001
mgross : 3/15/2001
alopez : 8/17/2000
terry : 8/14/2000
carol : 3/23/1999
alopez : 9/25/1998
carol : 9/25/1998
dkim : 7/23/1998
mark : 4/8/1996
mark : 8/25/1995
carol : 10/11/1994
mimadm : 5/18/1994
carol : 4/7/1993
carol : 9/25/1992
carol : 8/25/1992

* 189965

CCAAT/ENHANCER-BINDING PROTEIN, BETA; CEBPB


Alternative titles; symbols

C/EBP-BETA
INTERLEUKIN 6-DEPENDENT DNA-BINDING PROTEIN; IL6DBP
LIVER ACTIVATOR PROTEIN; LAP
LIVER-ENRICHED TRANSCRIPTIONAL ACTIVATOR PROTEIN
TRANSCRIPTION FACTOR 5; TCF5
NFIL6


HGNC Approved Gene Symbol: CEBPB

Cytogenetic location: 20q13.13     Genomic coordinates (GRCh38): 20:50,190,583-50,192,690 (from NCBI)


TEXT

Cloning and Expression

Interleukin-6 (147620), an important polypeptide hormone produced by various cell types, plays a central role in a variety of biologic phenomena. It modulates the immune response, is involved in the control of body temperature, and in the liver regulates the synthesis of plasma proteins, the 'acute phase' proteins. The IL6 receptor (IL6R; 147880) consists of 2 chains, a ligand-binding chain and a glycoprotein essential for transmembrane signaling which associates with the ligand-binding chain only after binding of the ligand. Two different IL6-responsive elements involved in the induction of acute phase proteins (IL6REs) were identified, one in the promoter of the haptoglobin and hemopexin genes and another in the promoter of the alpha-2 macroglobulin gene. The haptoglobin and hemopexin gene IL6RE sequence contains the recognition site for a family of nuclear proteins. One of these proteins, IL6-dependent DNA-binding protein (IL6DBP), is induced by IL6. It is identical to the liver-enriched transcriptional activator protein of Descombes et al. (1990). This protein was found to have a molecular weight of 32 kD and to stimulate transcription of chimeric genes containing the albumin D-promoter elements both in vivo and in vitro. LAP shared extensive sequence homology (71%) in its DNA-binding and leucine zipper domains with CCAAT/enhancer-binding protein (CEBPA; 116897). As a consequence, these 2 proteins show an indistinguishable DNA-binding specificity and readily heterodimerize. TCF5 is also identical to NF-IL6 (Akira et al., 1990). CEBPA and NF-IL6 (CEBPB, according to the nomenclature proposed by Cao et al., 1991) are 2 transcription factors belonging to a family of DNA-binding proteins predominantly characterized by a leucine zipper motif that mediates dimerization and a basic DNA binding domain. Notably, the CEBPA and CEBPB genes contain no introns.


Biochemical Features

Although collagen is known to enhance hepatocyte differentiation and hepatocytes produce collagen in vivo, the transcription factors responsible for collagen type I gene expression in hepatic cells is not known. Houglum et al. (1994) showed that LAP binds to the COL1A1 (120150) promoter at both reverse CCAAT motifs and activates transcription. Furthermore, they found an upstream element, collagen element I (-370/-344), which shares homology with the LAP binding cis-element of the albumin promoter (9 of 13 bp). This collagen element I stimulates transcription in both orientations and when placed in front of either a homologous or a heterologous chimeric report construct. Thus, LAP may be important in the expression of collagen and differentiated hepatocytes through both the promoter and the newly described upstream element.

Hormonal induction of growth-arrested 3T3-L1 preadipocytes rapidly activates expression of CEBPB. Acquisition of DNA-binding activity by CEBPB, however, is delayed until the cells synchronously enter the S phase of mitotic clonal expansion (MCE). After MCE, CEBPB activates expression of CEBPA and peroxisome proliferator-activated receptor gamma (PPARG; 601487), which then transcriptionally activate genes that give rise to the adipocyte phenotype. Zhang et al. (2004) studied the effect on adipogenesis of the CEBPB dominant-negative mutation that blocks CEBPB DNA binding by dimerizing with its leucine zipper. They provided evidence that the dominant-negative mutant prevented entry of CEBPB into the nucleus of 3T3-L1 preadipocytes and thereby blocks MCE and adipogenesis.


Gene Function

Menard et al. (2002) showed that Cebpb was expressed in mouse cortical progenitor cells and could induce expression of a reporter gene containing the minimal promoter of alpha-tubulin (TUBA1A; 602529), a neuron-specific gene. Gel and supershift assays confirmed that Cebpb bound the alpha-tubulin promoter in embryonic mouse brain. Menard et al. (2002) also showed that Cebpb was a downstream target of Mek (see 176872), which activated Rsk (see 601684) to phosphorylate Cebpb.

By computational analysis of the expression patterns of thousands of genes across hundreds of tumor specimens, Lamb et al. (2003) found that CEBP-beta participates in the consequences of cyclin D1 (CCND1; 168461) overexpression. Functional analysis confirmed the involvement of CEBPB in the regulation of genes affected by cyclin D1 and established CEBPB as a principal effector of cyclin D1 activity in human cancer.

By expression profiling of ALK (105590)-positive anaplastic large cell lymphomas (ALCLs), Piva et al. (2006) identified a large group of ALK-regulated genes. Functional RNA interference screening on a set of these transcriptional targets revealed that CEBPB and BCL2A1 (601056) were absolutely necessary to induce cell transformation and/or to sustain growth and survival of ALK-positive ALCL cells.

Dudaronek et al. (2007) showed that Ifnb (147720) induced expression of Lip, a truncated, dominant-negative isoform of Cebpb, and suppressed active simian immunodeficiency virus (SIV) replication in macaque macrophages. In a human monocyte cell line, IFNB induced phosphorylation of CUGBP1 (601074) and formation of CUGBP1-CEBPB mRNA complexes. Depletion of Cugbp1 in macaque macrophages via small interfering RNA showed that Cugbp1 was required for Ifnb-mediated induction of Lip and for Ifnb-mediated suppression of SIV replication. Dudaronek et al. (2007) concluded that CUGBP1 is a downstream effector of IFNB signaling in primary macrophages that plays an important role in innate immune responses controlling acute human immunodeficiency virus (HIV) or SIV replication in brain.

Using a cDNA complementation screen, Kinoshita and Taguchi (2008) identified NFIL6 as a host molecule that rendered primary CD4 (186940)-positive T cells permissive for HIV-1 replication. They found that NFIL6 regulated HIV-1 replication during reverse transcription after infection by binding to and inactivating the cytidine deaminase activity of APOBEC3G (607113) and also during gene transcription after integration. Binding and inactivation of APOBEC3G required ser288 in NFIL6. Overexpression of NFIL6 in nonpermissive cells enhanced HIV-1 replication, even in the absence of the HIV-1 protein Vif. Kinoshita and Taguchi (2008) proposed that NFIL6 evolved to negatively regulate APOBEC3G to limit DNA mutations, but that this mechanism backfires during HIV-1 infection, where it facilitates viral reverse transcription and replication.

Ishikawa et al. (2008) demonstrated that cAMP-induced binding of CEBP-beta to multiple motifs in the CYP19A1 (107910) promoter I.3/II region is a critical mechanism regulating aromatase expression in leiomyoma (see 150699) smooth muscle cells in primary culture. The authors concluded that definition of this mechanism further may assist in designing inhibitors of aromatase specific for leiomyoma tissue.

Kajimura et al. (2009) demonstrated that PRDM16 (605557) forms a transcriptional complex with the active form of C/EBP-beta, acting as a critical molecular unit that controls the cell fate switch from myoblastic precursors to brown fat cells. Forced expression of PRDM16 and C/CEBP-beta was sufficient to induce a fully functional brown fat program in naive fibroblastic cells, including skin fibroblasts from mouse and man. Transplantation of fibroblasts expressing these 2 factors into mice gave rise to an ectopic fat pad with the morphologic and biochemical characteristics of brown fat. Like endogenous brown fat, this synthetic brown fat tissue acted as a sink for glucose uptake, as determined by positron emission tomography with fluorodeoxyglucose. Kajimura et al. (2009) concluded that the PRMD16-C/EBP-beta complex initiates brown fat formation from myoblastic precursors and may provide opportunities for the development of therapeutics for obesity and type 2 diabetes.

Carro et al. (2010) used reverse engineering and an unbiased interrogation of a glioma-specific regulatory network to reveal the transcriptional module that activates expression of mesenchymal genes in malignant glioma. Two transcription factors, C/EBP-beta and STAT3 (102582), emerged as synergistic initiators and master regulators of mesenchymal transformation. Ectopic coexpression of C/EBP-beta and STAT3 reprogrammed neural stem cells along the aberrant mesenchymal lineage, whereas elimination of the 2 factors in glioma cells led to collapse of the mesenchymal signature and reduced tumor aggressiveness. In human glioma, expression of C/EBP-beta and STAT3 correlated with mesenchymal differentiation and predicted poor clinical outcome. Carro et al. (2010) concluded that the activation of a small regulatory module is necessary and sufficient to initiate and maintain an aberrant phenotypic state in cancer cells.

Bostrom et al. (2010) found that expression of Cebpb in mice was significantly downregulated during cardiac hypertrophy induced by exercise endurance training, but not during pathologic cardiac hypertrophy. Knockdown of Cebpb by small interfering RNA in primary rat cardiomyocytes increased cell size, the rate of protein synthesis, and cell number. Coimmunoprecipitation analysis showed that Cebpb interacted with Srf (600589), and knockdown of Cebpb increased binding of Srf to the promoters of the critical cardiac genes alpha-MHC (MYH6; 160710) and Gata4 (600576). Expression of Cited4 (606815) increased robustly in exercised hearts, and its expression level was altered by Cebpb gain or loss of function in vitro. Knockdown of Cited4 completely abolished the effect of Cebpb reduction on cardiomyocyte proliferation.

Overexpression of P-cadherin (CDH3; 114021) has been associated with proliferative lesions of high histologic grade, decreased cell polarity, and poor survival of patients with breast cancer. In vitro studies showed that it can be upregulated by the antiestrogen drug ICI 182,780, suggesting that the lack of estrogen receptor-alpha (ESRA; 133430) signaling may responsible for the aberrant P-cadherin overexpression and for its role in inducing breast cancer cell invasion and migration. Albergaria et al. (2010) showed that ICI 182,780 was able to increase P-cadherin promoter activity, inducing high levels of the active chromatin marker H3 lysine-4 dimethylation (H3K4me2). Albergaria et al. (2010) also showed that CEBPB was able to upregulate P-cadherin promoter activity in breast cancer cells. Moreover, the expression of P-cadherin and CEBPB were highly associated in human breast carcinomas and linked with a worse prognosis in breast cancer patients. The authors concluded that epigenetic upregulation of P-cadherin by ICI 182,780 in MCF-7/AZ breast cancer cells occurs through chromatin remodeling at the CDH3 promoter, bringing forward the growing evidence that ESRA signaling abrogation by antiestrogens may be able to induce the expression of ESRA-repressed genes which, in the appropriate cell biology context, may contribute to a breast cancer cell invasion phenotype.


Mapping

By analysis of human/mouse somatic cell hybrids, Szpirer et al. (1991) assigned the TCF5 gene to human chromosome 20. By corresponding studies in rat/mouse hybrids, they localized the gene to rat chromosome 3. Hendricks-Taylor et al. (1992) mapped the human CEBPB gene to chromosome 20 by Southern blot analysis of Chinese hamster/human and mouse/human somatic cell hybrids and regionalized the gene to 20q13.1 by fluorescence in situ hybridization. Using interspecific backcross analysis, Jenkins et al. (1995) showed that the Cebpb gene maps to mouse chromosome 2.


Evolution

Lynch et al. (2011) showed that amino acid changes in the transcription factor CEBPB in the stem lineage of placental mammals changed the way it responds to cAMP/protein kinase A (PKA; see 176911) signaling. By functionally analyzing resurrected ancestral proteins, they identified 3 amino acid substitutions in an internal regulatory domain of CEBPB that are responsible for the novel function. These amino acid substitutions reorganize the location of key phosphorylation sites, introducing a new site and removing 2 ancestral sites, reversing the response of CEBPB to GSK-3-beta (605004)-mediated phosphorylation from repression to activation. Lynch et al. (2011) concluded that changing the response of transcription factors to signaling pathways can be an important mechanism of gene regulatory evolution.


Animal Model

To determine the role of C/EBP-beta in the regenerating liver, Greenbaum et al. (1998) examined the regenerative response after partial hepatectomy in mice that had a targeted disruption of the gene. Posthepatectomy, hepatocyte DNA synthesis was decreased to 25% of normal in the homozygous deficient mice. The reduced regenerative response was associated with a prolonged period of hypoglycemia that was independent of expression of C/EBP-alpha protein and gluconeogenic genes. The homozygous C/EBP-beta-deficient livers showed reduced expression of immediate-early growth-control genes. This study demonstrated that C/EBP is required for a normal proliferative response.

Wang et al. (2000) performed detailed biochemical experiments on CEBPB-deficient mice. They found that the deletion caused decreased plasma free fatty acid levels and increased insulin signal transduction, specifically in skeletal muscle, and that both contribute to increased whole-body insulin sensitivity.

Croniger et al. (2001) noted that there are 2 distinct phenotypes, A and B, in Cebpb-deficient mice. Phenotype A mice survive to adulthood but have hypoglycemia as well as lipid, amino acid, and immunologic deficiencies. Phenotype B mice survive only 2 hours after birth and display profound hypoglycemia in spite of above normal levels of hepatic glycogen. Croniger et al. (2001) detailed the metabolic consequences in Cebpb-deficient mice. In these mice, relatively small changes in the rate of hepatic cAMP degradation and a shift in the pattern of protein kinase A (PKA; see 176911) isoform gene expression result in a lower concentration of cAMP in the liver. More cAMP is required to activate PKA, and the result is a failure of the normal response to glucagon.

Upon activation by liver injury, hepatic stellate cells produce excessive fibrous tissue leading to cirrhosis. Buck et al. (2001) found that the hepatotoxin CCl4 induced activation of Rsk (601684), phosphorylation of Cebpb on thr217 (Cebpb-Pthr217), and proliferation of stellate cells in normal mice, but it caused apoptosis of these cells in Cebpb -/- or Cebpb-ala217 (a dominant-negative nonphosphorylatable mutant) transgenic mice. Both Cebpb-Pthr217 and the phosphorylation mimicked Cebpb-glu217, but not Cebpb-ala217; were associated with procaspase-1 (147678) and -8 (601763) in vivo and in vitro; and inhibited activation of these procaspases. These data suggested that Cebpb phosphorylation on thr217 creates a functional XEXD caspase substrate/inhibitor box (K-phospho-T(217)VD) that is mimicked by Cebpb-glu217 (KE(217)VD). Cebpb -/- and Cebpb-ala217 stellate cells were rescued from apoptosis by the cell-permeant KE(217)VD tetrapeptide or Cebpb-glu217.

A surge of luteinizing hormone (LH; see 152780) from the pituitary gland triggers ovulation, oocyte maturation, and luteinization for successful reproduction in mammals. Because the signaling molecules RAS (190020) and ERK1/2 (see 601795) are activated by an LH surge in granulosa cells of preovulatory follicles, Fan et al. (2009) disrupted Erk1/2 in mouse granulosa cells and provided in vivo evidence that these kinases are necessary for LH-induced oocyte resumption of meiosis, ovulation, and luteinization. In addition, biochemical analyses and selected disruption of the Cebpb gene in granulosa cells demonstrated that C/EBP-beta is a critical downstream mediator of ERK1/2 activation. Thus, Fan et al. (2009) concluded that ERK1/2 and C/EBP-beta constitute an in vivo LH-regulated signaling pathway that controls ovulation- and luteinization-related events.

Bostrom et al. (2010) stated that homozygous Cebpb deletion in mice results in pre- and perinatal lethality, but that Cebpb +/- mice are relatively normal. They found increased heart weight and cardiomyocyte hypertrophy in Cebpb +/- mice, similar to that found in wildtype mice following endurance training. Cebpb +/- mice displayed a clear increase in exercise capacity at baseline, but no hypertrophy following training. Cultured cardiomyocytes from Cebpb +/- mice proliferated more readily than wildtype cardiomyocytes. Cebpb +/- mice also showed resistance to pathologic cardiac hypertrophy and dysfunction caused by pressure overload. Knockdown of Cebpb in zebrafish caused an increase in cardiomyocyte cell number, but no change in cardiomyocyte size. Bostrom et al. (2010) concluded that reduced CEBPB activity during exercise contributes to physiologic cardiac hypertrophy.


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Contributors:
George E. Tiller - updated : 9/13/2013
Ada Hamosh - updated : 2/27/2012
Patricia A. Hartz - updated : 3/15/2011
Ada Hamosh - updated : 2/18/2010
Ada Hamosh - updated : 9/9/2009
Ada Hamosh - updated : 8/17/2009
John A. Phillips, III - updated : 4/23/2009
Paul J. Converse - updated : 3/24/2009
Paul J. Converse - updated : 12/18/2008
Ada Hamosh - updated : 10/28/2008
Patricia A. Hartz - updated : 1/25/2007
Patricia A. Hartz - updated : 5/8/2006
Victor A. McKusick - updated : 2/6/2004
Stylianos E. Antonarakis - updated : 11/13/2001
Paul J. Converse - updated : 3/15/2001
Ada Hamosh - updated : 8/14/2000
Victor A. McKusick - updated : 9/25/1998

Creation Date:
Victor A. McKusick : 10/26/1990

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