Alternative titles; symbols
HGNC Approved Gene Symbol: CEBPD
Cytogenetic location: 8q11.21 Genomic coordinates (GRCh38): 8:47,736,913-47,738,164 (from NCBI)
CEPD belongs to the CCAAT/enhancer-binding protein family of transcription factors, which are characterized by a basic DNA-binding domain linked to heptad leucine repeats that mediate dimerization (Cleutjens et al., 1993).
Using PCR, Cleutjens et al. (1993) isolated a cDNA homologous to mouse C/EBP-delta (CRP3) and rat Celf from a prostate cDNA library. The deduced protein contains 269 amino acids. A genomic clone containing the entire human CEBPD gene was isolated using a cDNA fragment as a probe.
Menard et al. (2002) showed that Cebpd was expressed in mouse cortical progenitor cells. Cebpd induced expression of a reporter gene containing the minimal promoter of alpha-tubulin (TUBA1A; 602529), a neuron-specific gene.
Corneal stem cells are segregated in the basal layer of the limbus, which is the vascularized zone encircling the cornea and separating it from the bulbar conjuctiva. Barbaro et al. (2007) found that CEBPD, BMI1 (164831), and an isoform of p63 (TP63; 603273) called delta-N p63-alpha were expressed in quiescent human corneal limbal stem cells in vivo and in limbal holoclone-forming cells in vitro. Expression of CEBPD was restricted to a subset of delta-N p63-alpha-positive cells that were mitotically quiescent both in vivo and in vitro. Upon corneal injury, a fraction of these cells switched off CEBPD and BMI1 and proliferated and differentiated into mature corneal cells. Forced CEBPD expression inhibited growth of limbal colonies and increased the cell cycle length by activating p27(KIP1) (CDKN1B; 600778) and p57(KIP2) (CDKN1C; 600856). CEBPD, but not delta-N p63-alpha, indefinitely promoted holoclone self-renewal and prevented clonal evolution, suggesting that self-renewal and proliferation in limbal stem cells are distinct, but related, processes. Chromatin immunoprecipitation analysis showed the CEBPD was recruited to intron 3 of the TP63 gene and to regions upstream of the involucrin (IVL; 147360), p27(KIP1), p57(KIP2), and p16(INK4A) (CDKN2A; 600160) promoters. Barbaro et al. (2007) concluded that CEBPD plays a key role in regulating the cell cycle and self-renewal properties of human corneal limbal stem cells. They proposed that CEBPD induces mitotic quiescence through p27(KIP1) and p57(KIP2) and preserves proliferative potential through regulation of delta-N p63-alpha.
By fluorescence in situ hybridization, Cleutjens et al. (1993) assigned the CEBPD gene to 8q11. The chromosomal localization was confirmed by analysis of a panel of human/hamster somatic cell hybrid DNA samples containing various portions of chromosome 8 with a CEBPD-specific STS. They positioned the CEBPD gene between the gene for tissue plasminogen activator (173370) and the MOS oncogene (190060). The murine gene is located on mouse chromosome 16 (cited by Williams et al., 1991).
Kirchgessner et al. (1995) established a synteny group between human 8q11, containing the gene for the p350 subunit of DNA-activated protein kinase (600899) and the CEBPD gene, and the centromeric region of mouse chromosome 16.
By interspecific backcross analysis, Jenkins et al. (1995) demonstrated that the Cebpd gene maps to mouse chromosome 16. The assignment to mouse chromosome 16 defines a new region of homology with human chromosome 8. By cell hybrid and fluorescence in situ hybridization mapping, Wood et al. (1995) placed both CEBPD and FGFR1 (136350) within the chromosome region 8p11.2-p11.1.
Gigliotti et al. (2003) stated that Cebpd deletion in mice leads to relatively subtle abnormalities, including slightly impaired adipocyte differentiation, and to learning and memory alterations that enhance contextual fear-conditioned responses. They found that adult nulliparous Cebpd -/- female mice exhibited excessive mammary ductal branching and increased total mammary epithelium compared with nulliparous wildtype females. These changes resulted from increased proliferation of mammary epithelial cells during the normal estrous cycle. Reproduction, lactation, and mammary gland involution were essentially normal in Cebpd -/- females.
Thangaraju et al. (2006) found that renal expression of the Na(+)/lactate cotransporters Slc5a8 (608044) and Slc5a12 (612455) was reduced in Cebpd +/- mice and was almost completely ablated in Cebpd -/- mice. Expression of other renal transporters, including the uric acid transporter Urat1 (SLC22A12; 607096), remained normal in Cebpd -/- mice, and expression of Slc5a8 and Slc5a12 in brain and intestine was unaffected by Cebpd deletion. Reporter gene assays using the promoter region of human SLC5A8 and SLC5A12 confirmed that CEBPD induced expression of these transporters.
Barbaro, V., Testa, A., Di Iorio, E., Mavilio, F., Pellegrini, G., De Luca, M. C/EBP-delta regulates cell cycle and self-renewal of human limbal stem cells. J. Cell Biol. 177: 1037-1049, 2007. [PubMed: 17562792] [Full Text: https://doi.org/10.1083/jcb.200703003]
Cleutjens, C. B. J. M., van Eekelen, C. C. E. M., van Dekken, H., Smit, E. M. E., Hagemeijer, A., Wagner, M. J., Wells, D. E., Trapman, J. The human C/EBP-delta (CRP3/CELF) gene: structure and chromosomal localization. Genomics 16: 520-523, 1993. [PubMed: 8314590] [Full Text: https://doi.org/10.1006/geno.1993.1220]
Gigliotti, A. P., Johnson, P. F., Sterneck, E., DeWille, J. W. Nulliparous CCAAT/enhancer binding protein-delta (C/EBP-delta) knockout mice exhibit mammary gland ductal hyperlasia (sic). Exp. Biol. Med. 228: 278-285, 2003.
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] [Full Text: https://doi.org/10.1006/geno.1995.1150]
Kirchgessner, C. U., Patil, C. K., Evans, J. W., Cuomo, C. A., Fried, L. M., Carter, T., Oettinger, M. A., Brown, J. M. DNA-dependent kinase (p350) as a candidate gene for the murine SCID defect. Science 267: 1178-1183, 1995. [PubMed: 7855601] [Full Text: https://doi.org/10.1126/science.7855601]
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] [Full Text: https://doi.org/10.1016/s0896-6273(02)01026-7]
Thangaraju, M., Ananth, S., Martin, P. M., Roon, P., Smith, S. B., Sterneck, E., Prasad, P. D., Ganapathy, V. c/ebp-delta null mouse as a model for the double knock-out of slc5a8 and slc5a12 in kidney. J. Biol. Chem. 281: 26769-26773, 2006. [PubMed: 16873376] [Full Text: https://doi.org/10.1074/jbc.C600189200]
Williams, S. C., Cantwell, C. A., Johnson, P. F. A family of C/EBP-related proteins capable of forming covalently linked leucine zipper dimers in vitro. Genes Dev. 5: 1553-1567, 1991. [PubMed: 1884998] [Full Text: https://doi.org/10.1101/gad.5.9.1553]
Wood, S., Schertzer, M., Yaremko, M. L. Sequence identity locates CEBPD and FGFR1 to mapped human loci within proximal 8p. Cytogenet. Cell Genet. 70: 188-191, 1995. [PubMed: 7789168] [Full Text: https://doi.org/10.1159/000134030]