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

• A significant psychopathology was found in the NFI patients, p <0.001 [6].

High impact information on NFIC

• However, NF-I specifically prevented the repression of DNA replication that occurred when the template was preassembled into chromatin [7].
• The CTF C-terminal region consists of an unusual type of transcriptional activation domain containing approximately 25% proline residues [8].
• We studied a model viral chromosome containing a single binding site for the cellular transcriptional activator, nuclear factor I (NF-I/CTF), located adjacent to the replication origin [7].
• Purified NF-I had little effect on the replication efficiency in the standard SV40 cell-free system when the template was introduced as naked DNA [7].
• The proline-rich transcriptional activator of CTF/NF-I is distinct from the replication and DNA binding domain [8].

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

• Repression by NFI-C is cell type-dependent and occurs in HeLa and COS-1 cells but not 293 or JEG-3 cells [16].
• In contrast, fibroblasts, where the enhancer is inactive, express high levels of NFI from the NFI-X gene [2].
• 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 [17].
• The data showed that Brg1 was closely co-localized with NF1/CTF and RNAP II in HeLa cells [18].
• Overexpression of NFI-C in NIH-3T3 cells results in an increase in SMUG1 enzyme activity [19].

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

• Here we show that restoration of the DNA-binding activity of oxidized NFI-C can be catalyzed in vitro by the cellular enzyme thioltransferase (glutaredoxin) coupled to GSH and GSSG reductase [25].

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].

References