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Gene Review

NFIC  -  nuclear factor I/C (CCAAT-binding...

Homo sapiens

Synonyms: CCAAT-box-binding transcription factor, CTF, CTF5, NF-I, NF-I/C, ...
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Disease relevance of NFIC

  • Originally identified as factors implicated in the replication of adenovirus, this group of proteins (CTF/NF1-A, -B, -C, and -X) is now known to be involved in the regulation of several genes [1].
  • Previous studies of the epithelial specificity of the human papillomavirus type 16 (HPV-16) enhancer pointed out an important role of nuclear factor I (NFI) [2].
  • Taken together, our results reveal an estrogen-regulated combinatorial network including cell-specific cis- and trans-regulators of CCND1 expression where ERalpha collaborates with other transcription factors associated with the ER-positive breast cancer phenotype, including FoxA1 and NFIC [3].
  • Specific therapeutic goals were established for each patient, and the NFIC (now CCFA)-IOIBD index of Crohn's disease activity was calculated pre- and post-therapy [4].
  • A mammary cell-specific enhancer in mouse mammary tumor virus DNA is composed of multiple regulatory elements including binding sites for CTF/NFI and a novel transcription factor, mammary cell-activating factor [5].

Psychiatry related information on NFIC


High impact information on NFIC


Chemical compound and disease context of NFIC

  • The Nuclear Factor I (NFI) family of DNA-binding proteins is essential for adenovirus DNA replication and the transcription of many cellular genes [9].
  • This demonstrates that the promoter of this human hsp70 gene interacts with at least two positive transcriptional activators, CTF, which is required for CCAAT-box-dependent transcription as in other promoters such as those of globin and herpes simplex virus thymidine kinase genes, and HSTF, which is involved in heat inducibility [10].
  • NFI-C proteins containing mutations in any of four conserved Cys residues, expressed in Escherichia coli or in vitro, did not bind to DNA [11].
  • Using the hepatoma cell line HepG2, we report that the trans-activating function of the nuclear factor I/CCAAT box transcription factor (NFI/CTF-1) is, on the contrary, repressed by various stress conditions, including inflammatory cytokine treatment, glutathione depletion, heat and osmotic shocks, and chemical stress [12].
  • We screened a porcine liver, genomic DNA library in phage EMBL3A with synthetic oligonucleotides derived from tryptic and cyanogen-bromide peptide sequences obtained from purified NFI protein [13].

Biological context of NFIC

  • CTF/NF1 is a family of transcription factors that contributes to constitutive and cell-type specific gene expression [1].
  • NFI/CTF is a family of polypeptides involved in stimulating the initiation of adenovirus DNA replication and the activation of transcription driven by RNA polymerase II [14].
  • Cloning and functional analysis of spliced isoforms of human nuclear factor I-X: interference with transcriptional activation by NFI/CTF in a cell-type specific manner [2].
  • In addition, CTF5 is even more active than CTF7, which lacks exons 7-9 [14].
  • These NFI proteins cooperate with AP-1, Myc, and other transcription factors in regulating transcription of numerous cellular and viral genes [15].

Anatomical context of NFIC


Associations of NFIC with chemical compounds

  • Repression is DNA binding-independent as a deletion construct expressing the NH2-terminal 160 residues of NFI-C represses but does not bind DNA [16].
  • Nuclear Factor I (NFI) proteins constitute a family of dimeric DNA-binding proteins with very similar, possibly identical, DNA-binding specificity [20].
  • Interestingly, even in BCC, CCND1 levels and proliferation are tightly controlled by E2 through the establishment of a negative feedforward loop involving the induction of NFIC, a putative tumor suppressor capable of directly repressing CCND1 transcription [3].
  • Synthesis of the 74-kDa NFIC was also inhibited in this setting by tunicamycin [21].
  • We show that the 74-kDa NFIC binds specifically to concanavalin A (ConA) and that this binding can be reversed by the specific ConA ligands, methyl alpha-D-mannopyranoside and methyl alpha-D-glucopyranoside [21].

Physical interactions of NFIC

  • Chromatin immunoprecipitation also showed that NFI proteins are bound to the GABRA6 promoter in these cells in vivo [22].
  • Western immunoblot and supershift analysis shows that exogenously introduced CTF-1 proteins form different heterodimer complexes with the given subset of endogenous NFI proteins in epithelial or fibroblast cells [23].
  • To determine if this strict positional constraint was a result of interactions between genome-bound proteins, we used the DNA-binding domain of NFI immobilized on Sepharose as an affinity matrix to examine binding of the adenovirus DNA polymerase and preterminal protein [24].

Enzymatic interactions of NFIC


Regulatory relationships of NFIC

  • We conclude that RA induction of the secretin gene in neuronal cells is regulated by the combined actions of reducing Sp3 and increasing NFI-C expression [26].

Other interactions of NFIC

  • Here we describe a naturally truncated isoform, NFI-B3, which is derived from the human NFI-B gene, in addition to characterizing further human NFI-B1 and NFI-B2, two differentially spliced variants previously isolated from hamster and chicken [27].
  • However, repression by NFI-C occurs with only a subset of glucocorticoid-responsive promoters, as the chimeric NFIGREbeta-gal promoter that is activated by GR is not repressed by NFI-C [16].
  • While the transcriptional activation domain of NFI-X2, functionally tested as GAL4-fusion protein in epithelial and fibroblast cells, activates transcription from promoter as well as enhancer position similar to NFI/CTF-1, the activation domain of NFI-X1 fails to activate transcription from enhancer position [2].
  • To date, only a porcine NFI-C gene has been cloned, and the gene structures of the other NF1 proteins have not yet been identified [28].
  • Electrophoretic mobility shift assays revealed that transcription factors of the hepatocyte nuclear factor-3 (HNF-3) and nuclear factor-I (NFI/CTF) families were able to bind to this region in a sequence-specific manner [17].

Analytical, diagnostic and therapeutic context of NFIC

  • Gel shift analysis indicated that NFI-B3 disrupts the function of other NFI proteins by reducing their DNA binding activity by heterodimer formation [27].
  • Sequence alignments of NFI proteins from chicken and various mammalian species provide evidence for a common genetic equipment among higher eukaryotes, in which several related genes, employing each differential RNA splicing generate an unexpectedly large family of diverse NFI proteins [29].
  • Using microsequencing data from peptides of isolated proteins and PCR supported cloning, we have derived four cDNAs for NFI/TGGCA proteins, which are encoded by three separate chicken genes [29].
  • The presence of NF-1C2 (CTF2) and CTF5 in NCI-H295A cells was demonstrated by RT-PCR and sequencing [30].
  • NFI-X expression, examined by Northern blots, shows strong cell-type specific variation in comparison with NFI/CTF [2].


  1. The interaction between the forkhead thyroid transcription factor TTF-2 and the constitutive factor CTF/NF-1 is required for efficient hormonal regulation of the thyroperoxidase gene transcription. Ortiz, L., Aza-Blanc, P., Zannini, M., Cato, A.C., Santisteban, P. J. Biol. Chem. (1999) [Pubmed]
  2. Cloning and functional analysis of spliced isoforms of human nuclear factor I-X: interference with transcriptional activation by NFI/CTF in a cell-type specific manner. Apt, D., Liu, Y., Bernard, H.U. Nucleic Acids Res. (1994) [Pubmed]
  3. A cell-type-specific transcriptional network required for estrogen regulation of cyclin D1 and cell cycle progression in breast cancer. Eeckhoute, J., Carroll, J.S., Geistlinger, T.R., Torres-Arzayus, M.I., Brown, M. Genes Dev. (2006) [Pubmed]
  4. Long-term experience with 6-mercaptopurine in the treatment of Crohn's disease. Korelitz, B.I., Adler, D.J., Mendelsohn, R.A., Sacknoff, A.L. Am. J. Gastroenterol. (1993) [Pubmed]
  5. A mammary cell-specific enhancer in mouse mammary tumor virus DNA is composed of multiple regulatory elements including binding sites for CTF/NFI and a novel transcription factor, mammary cell-activating factor. Mink, S., Härtig, E., Jennewein, P., Doppler, W., Cato, A.C. Mol. Cell. Biol. (1992) [Pubmed]
  6. A psychiatric 12-year follow-up of adult patients with neurofibromatosis type 1. Zöller, M.E., Rembeck, B. Journal of psychiatric research. (1999) [Pubmed]
  7. Transcriptional activator nuclear factor I stimulates the replication of SV40 minichromosomes in vivo and in vitro. Cheng, L., Kelly, T.J. Cell (1989) [Pubmed]
  8. The proline-rich transcriptional activator of CTF/NF-I is distinct from the replication and DNA binding domain. Mermod, N., O'Neill, E.A., Kelly, T.J., Tjian, R. Cell (1989) [Pubmed]
  9. Exon structure of the nuclear factor I DNA-binding domain from C. elegans to mammals. Fletcher, C.F., Jenkins, N.A., Copeland, N.G., Chaudhry, A.Z., Gronostajski, R.M. Mamm. Genome (1999) [Pubmed]
  10. Two transcriptional activators, CCAAT-box-binding transcription factor and heat shock transcription factor, interact with a human hsp70 gene promoter. Morgan, W.D., Williams, G.T., Morimoto, R.I., Greene, J., Kingston, R.E., Tjian, R. Mol. Cell. Biol. (1987) [Pubmed]
  11. Four conserved cysteine residues are required for the DNA binding activity of nuclear factor I. Novak, A., Goyal, N., Gronostajski, R.M. J. Biol. Chem. (1992) [Pubmed]
  12. Nuclear factor I/CCAAT box transcription factor trans-activating domain is a negative sensor of cellular stress. Morel, Y., Coumoul, X., Nalpas, A., Barouki, R. Mol. Pharmacol. (2000) [Pubmed]
  13. Isolation and characterization of the porcine nuclear factor I (NFI) gene. Meisterernst, M., Rogge, L., Donath, C., Gander, I., Lottspeich, F., Mertz, R., Dobner, T., Föckler, R., Stelzer, G., Winnacker, E.L. FEBS Lett. (1988) [Pubmed]
  14. CTF5--a new transcriptional activator of the NFI/CTF family. Wenzelides, S., Altmann, H., Wendler, W., Winnacker, E.L. Nucleic Acids Res. (1996) [Pubmed]
  15. Nuclear factor I interferes with transformation induced by nuclear oncogenes. Schuur, E.R., Kruse, U., Iacovoni, J.S., Vogt, P.K. Cell Growth Differ. (1995) [Pubmed]
  16. Nuclear factor I-mediated repression of the mouse mammary tumor virus promoter is abrogated by the coactivators p300/CBP and SRC-1. Chaudhry, A.Z., Vitullo, A.D., Gronostajski, R.M. J. Biol. Chem. (1999) [Pubmed]
  17. Promoter region of the human gene coding for beta-chain of C4b binding protein. Hepatocyte nuclear factor-3 and nuclear factor-I/CTF transcription factors are required for efficient expression of C4BPB in HepG2 cells. Arenzana, N., Rodríguez de Córdoba, S. J. Immunol. (1996) [Pubmed]
  18. BAF complex is closely related to and interacts with NF1/CTF and RNA polymerase II in gene transcriptional activation. Zhao, L.H., Ba, X.Q., Wang, X.G., Zhu, X.J., Wang, L., Zeng, X.L. Acta Biochim. Biophys. Sin. (Shanghai) (2005) [Pubmed]
  19. The transcription factor, NFI/CTF plays a positive regulatory role in expression of the hSMUG1 gene. Elateri, I., Muller-Weeks, S., Caradonna, S. DNA Repair (Amst.) (2003) [Pubmed]
  20. Chromosomal localization of the four genes (NFIA, B, C, and X) for the human transcription factor nuclear factor I by FISH. Qian, F., Kruse, U., Lichter, P., Sippel, A.E. Genomics (1995) [Pubmed]
  21. Transcription factor NFIC undergoes N-glycosylation during early mammary gland involution. Kane, R., Murtagh, J., Finlay, D., Marti, A., Jaggi, R., Blatchford, D., Wilde, C., Martin, F. J. Biol. Chem. (2002) [Pubmed]
  22. A role for nuclear factor I in the intrinsic control of cerebellar granule neuron gene expression. Wang, W., Stock, R.E., Gronostajski, R.M., Wong, Y.W., Schachner, M., Kilpatrick, D.L. J. Biol. Chem. (2004) [Pubmed]
  23. Nuclear factor I and epithelial cell-specific transcription of human papillomavirus type 16. Apt, D., Chong, T., Liu, Y., Bernard, H.U. J. Virol. (1993) [Pubmed]
  24. Interactions between the adenovirus type 2 DNA polymerase and the DNA binding domain of nuclear factor I. Bosher, J., Robinson, E.C., Hay, R.T. New Biol. (1990) [Pubmed]
  25. Thioltransferase (glutaredoxin) reactivates the DNA-binding activity of oxidation-inactivated nuclear factor I. Bandyopadhyay, S., Starke, D.W., Mieyal, J.J., Gronostajski, R.M. J. Biol. Chem. (1998) [Pubmed]
  26. Retinoic acid activates human secretin gene expression by Sp proteins and nuclear factor I in neuronal SH-SY5Y cells. Lee, L.T., Tan-Un, K.C., Lin, M.C., Chow, B.K. J. Neurochem. (2005) [Pubmed]
  27. NFI-B3, a novel transcriptional repressor of the nuclear factor I family, is generated by alternative RNA processing. Liu, Y., Bernard, H.U., Apt, D. J. Biol. Chem. (1997) [Pubmed]
  28. Genomic organization of the rat nuclear factor I-A gene. Xu, M., Osada, S., Imagawa, M., Nishihara, T. J. Biochem. (1997) [Pubmed]
  29. Chicken NFI/TGGCA proteins are encoded by at least three independent genes: NFI-A, NFI-B and NFI-C with homologues in mammalian genomes. Rupp, R.A., Kruse, U., Multhaup, G., Göbel, U., Beyreuther, K., Sippel, A.E. Nucleic Acids Res. (1990) [Pubmed]
  30. NF-1C, Sp1, and Sp3 are essential for transcription of the human gene for P450c17 (steroid 17alpha-hydroxylase/17,20 lyase) in human adrenal NCI-H295A cells. Lin, C.J., Martens, J.W., Miller, W.L. Mol. Endocrinol. (2001) [Pubmed]
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