Disease relevance of IFI6

• Interestingly, 6-16 is expressed at high levels in gastric cancer cell lines and tissues [1].
• In a previously targeted clone derived from the fibrosarcoma cell line HT1080, the replacement construct underwent HR with either the modified or the unmodified 6-16 allele [2].
• Plaque assays of infected 6-16-/- cells showed that expression of the 6-16 gene was not required for the induction by interferon of an antiviral state against encephalomyocarditis virus, semliki forest virus or cocal virus [2].
• Treatment of human hepatoma cells with IL-28A activates the JAK-STAT signaling pathway and induces the expression of some interferon-stimulated genes (ISGs), such as 6-16 and 1-8U [3].
• The six most constantly expressed genes are (1) G1P3, (2) POU domain, class 3, transcription factor 1, (3) myxovirus resistance 2, (4) lysosomal-associated multispanning membrane protein-5, (5) hemoglobin alpha 2 and (6) hemoglobin beta [4].

High impact information on IFI6

• Telomeric DNA was targeted to the 6-16 gene on the short arm of chromosome 1 in a human cell line [5].
• Chromatin immunoprecipitation assays demonstrated the recruitment of actin to the promoter region of the interferon-gamma-inducible MHC2TA gene as well as the interferon-alpha-inducible G1P3 gene [6].
• A 14 bp interferon (IFN)-stimulated response element (ISRE) from 6-16, a human gene regulated by alpha-IFN, confers IFN inducibility on a heterologous thymidine kinase promoter [7].
• A 39 bp double-stranded oligonucleotide corresponding to a 5' region of 6-16 which includes the ISRE competes for factors required for gene expression by alpha-IFN in transfected cells and a single base change (A-11 to C) within the ISRE (GGGAAAATGAAACT) abolishes this competition [7].
• 1046 base-pairs (bp) of genomic DNA spanning the first exon of the human alpha/beta-interferon (IFN)-inducible gene 6-16 have been analysed for their role in induction [8].

Chemical compound and disease context of IFI6

• One of exceptional gastric cancer cell line, TMK-1, which do not express detectable 6-16, is sensitive to apoptosis induced by cycloheximide (CHX), 5-fluorouracil (5-FU) and serum-deprivation [1].

Biological context of IFI6

• Interferon response element of the human gene 6-16 [8].
• After transfection of the human genomic cosmid into mouse Ltk- cells, human 6-16 mRNA is expressed in response to mouse alpha- and beta- but not gamma-interferons with the same kinetics and dose-response as in the human cells [9].
• The 6-16 minisatellite is therefore an example of tandemly repeated DNA that has a role in gene expression and may provide a useful in vivo system for the analysis of 5' splice site choice and minisatellite biology [10].
• Similar minisatellites from nonhuman primates are described and also appear to modulate splicing of a 6-16 transcript [10].
• A transcriptional bias in the 6-16 promoter/enhancer accounts in large part for the differential response of 6-16 to the two interferons [11].

Anatomical context of IFI6

• Expression of an interferon inducible gene 6-16, G1P3, increases not only in type I interferon-treated cells but also in human senescent fibroblasts [1].
• Here we report that 6-16 is 34 kDa glycosylated protein and localized at mitochondria [1].
• The regions of several genes (IFI-56K, HLA-A3, HLA-DR and 6-16) containing the (putative) ISRE (Interferon Stimulatable Response Element) were tested for their ability to be recognized by HeLa cells nuclear extract proteins [12].
• Several IFN-alpha-inducible mRNAs, e.g., 561, 6-16, 1-8, and 2A, were induced much more strongly in granulocytes than in macrophages or in undifferentiated cells [13].
• These marked differences were not due to a selective overall increase in B cell response only to some IFN subtypes, as all those tested similarly induced the IFN-inducible genes 6-16 and HLA class I. Our results show that human B cells must respond to type I IFN via two distinct pathways [14].

Associations of IFI6 with chemical compounds

• Previously we described human cell line 2fTGH, in which expression of guanine phosphoribosyltransferase is tightly controlled by the upstream region of interferon (IFN)-stimulated human gene 6-16 [15].
• Following therapy with alpha-interferon, 2'-5' oligoadenylate synthetase, ISG-54, and 6-16 transcripts were discerned in all patients regardless of their response to interferon [16].
• In 2 genes (IFITM1, 6-16), the response to IFN-alpha could be restored by treatment with lamivudine [17].
• In GM2767 cells, 2-aminopurine inhibited induction of mRNAs 561 and 6-16 by double-stranded RNA but not by alpha interferon [18].
• In addition, we demonstrate that ISF21 is necessary for transcriptional activation of 2'-5'-oligoadenylate synthetase, 6-16, and guanylate-binding protein gene promoter reporter constructs, which are mediated by several signaling pathways [19].

Other interactions of IFI6

• Furthermore, the 9-27 (GGAAATAGAAACT) and 6-16 (GGGAAAATGAAACT) ISREs can each confer a response to both types of IFN when placed on the 5' side of a marker gene [20].
• Since the 6-16 gene does not normally respond to IFN-gamma, the context of the ISRE must determine the specificity of the response [20].
• Peripheral blood samples were collected prior to and 1 to 7 days after starting interferon therapy and analyzed for the expression of 2'-5' oligoadenylate synthetase, ISG-15, ISG-54, and 6-16 transcripts [16].
• Nucleotide sequence features of the human interferon-inducible gene 6-16 are described and include, within a CpG island, a partially expressed minisatellite consisting of 26 tandemly repeated dodecanucleotides [10].
• Moreover, 6/25 genes were up-regulated in 40% of MS twins and one gene, interferon alpha-inducible protein (clone IFI-6-16) (G1P3), in 50% of them [4].

Analytical, diagnostic and therapeutic context of IFI6

• In electrophoretic mobility-shift assays the 6-16 and (2'-5') oligoadenylate synthetase ISRE competed approximately equivalently for E and M [21].
• Using the techniques of differential display reverse transcription-polymerase chain reaction (DD RT-PCR) and Northern blot analysis, we identified that an interferon-inducible gene 6-16 is regulated in the ORS cells when cultured with the DP-conditioned medium [22].
• We describe gene targeting experiments involving a human cell line (RAN10) containing, in addition to its endogenous alleles, two ectopic alleles of the interferon-inducible gene 6-16 [23].

References