Structural analysis of the rabbit TNF locus, containing the genes encoding TNF-β(lymphotoxin) and TNF-α(tumor necrosis factor)

Shakhov, Alexander N.; Kuprash, Dmitry V.; Azizov, Mekhman; Jongeneel, C. Victor; Nedospasov, Sergei A.

doi:10.1016/0378-1119(90)90364-w

Cited by 39 publications

(13 citation statements)

References 31 publications

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“…A number of NF-B-like binding motifs are located between the start of transcription of the TNF gene and the 3Ј terminus of the lymphotoxin-␣ gene: they are here denoted B1 (Ϫ873 to Ϫ864 nt), B2 (Ϫ627 to Ϫ618 nt), B2a (Ϫ598 to Ϫ589 nt), CK-1 (Ϫ213 to Ϫ204 nt (17)), and B3 (Ϫ98 to Ϫ89 nt). It is worth noting that site B2 is 100% conserved between mouse, rabbit, and human TNF promoters (18). Moreover, LPS induces nuclear translocation of NF-B in human monocytes, and LPS-inducible TNF expression is suppressed by specific inhibitors of NF-B mobilization (19,20).…”

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confidence: 99%

Complex NF-κB Interactions at the Distal Tumor Necrosis Factor Promoter Region in Human Monocytes

Udalova¹,

Knight²,

Vidal³

et al. 1998

Journal of Biological Chemistry

116

110

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We describe a dense cluster of DNA-protein interactions located 600 nucleotides upstream of the transcriptional start site of the human tumor necrosis factor (TNF) gene. This area was identified as being of potential importance for lipopolysaccharide-inducible TNF expression in the human monocyte cell line Mono Mac 6, based on reporter gene analysis of point mutations at a number of nuclear factor B (NF-B)-like motifs within the human TNF promoter region. The area contains two NF-B sites, which are here shown by DNase I and methylation interference footprinting to flank a novel binding site. UV cross-linking studies reveal that the novel site can also bind NF-B as well as an unknown protein(s) of approximately 40 kDa. We show that these three adjacent B-binding sites differ markedly in their relative affinities for p50/p50, p65/p65, and p65/p50, yet this 39-nucleotide segment of DNA appears capable of binding up to three NF-B heterodimers simultaneously. Reporter gene studies indicate that each element of the cluster contributes to lipopolysaccharideinduced transcriptional activation in Mono Mac 6 cells. These findings suggest that NF-B acts in a complex manner to activate TNF transcription in human monocytes.A fundamental problem in infectious disease is to understand the mechanisms by which microbial stimuli such as bacterial lipopolysaccharide (LPS) 1 regulate the expression of human inflammatory mediators such as tumor necrosis factor-␣ (TNF). Production of TNF by macrophages and monocytes occurs early in infection and orchestrates much of the subsequent inflammatory response (1). Because excessive production of TNF is responsible for many of the pathological consequences of severe infection, its regulation is critical. This occurs at both the transcriptional and post-transcriptional levels (2), with transcriptional regulation showing specificity for both stimulus and cell type (3). Reporter gene studies of the human TNF promoter using a range of stimuli and cell types have identified a number of regulatory elements upstream of the transcriptional start site, mostly within the proximal 200 base pairs (4 -13). However, we still have a poor understanding of the precise regulatory events that are responsible for the rapid induction of high level TNF expression in human monocytes and macrophages during acute bacterial infection.Much debate has centered on the role of nuclear factor-B (NF-B) in transcriptional activation of the human TNF gene in monocytes. Although there is strong evidence that murine TNF expression is influenced by a number of NF-B binding sites (14 -16), the situation in humans is less clear. Several lines of circumstantial evidence suggest that NF-B could play an important role. A number of NF-B-like binding motifs are located between the start of transcription of the TNF gene and the 3Ј terminus of the lymphotoxin-␣ gene: they are here denoted B1 (Ϫ873 to Ϫ864 nt), B2 (Ϫ627 to Ϫ618 nt), B2a (Ϫ598 to Ϫ589 nt), CK-1 (Ϫ213 to Ϫ204 nt (17)), and B3 (Ϫ98 to Ϫ89 nt). It is worth noting that site B2...

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mentioning

confidence: 99%

Complex NF-κB Interactions at the Distal Tumor Necrosis Factor Promoter Region in Human Monocytes

Udalova¹,

Knight²,

Vidal³

et al. 1998

Journal of Biological Chemistry

116

110

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“…It regulates a panel of genes that collectively play pro-survival and anti-apoptotic roles [26,27]. It also controls the expression of genes linked with invasion, angiogenesis, and metastasis of cancer, including the matrix metalloproteinase ( MMP ) family [28,29] and chemokine (C-X-C motif) ligand ( CXCL ) family genes [30,31].…”

Section: Introductionmentioning

confidence: 99%

Ubiquitin-conjugating enzyme complex Uev1A-Ubc13 promotes breast cancer metastasis through nuclear factor-кB mediated matrix metalloproteinase-1 gene regulation

Shen

Zhang

et al. 2014

Breast Cancer Res

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IntroductionUEV1A encodes a ubiquitin-conjugating enzyme variant (Ubc13), which is required for Ubc13-catalyzed Lys63-linked polyubiquitination of target proteins and nuclear factor κB (NF-кB) activation. Previous reports have correlated the level of UEV1A expression with tumorigenesis; however, the detailed molecular events leading to tumors particularly breast cancer and metastasis are unclear. This study is to investigate roles of different UEV1 splicing variants, and its close homolog MMS2, in promoting tumorigenesis and metastasis in breast cancer cells.MethodsWe experimentally manipulated the UEV1 and MMS2 levels in MDA-MB-231 breast cancer cells and monitored their effects on cell invasion and migration, as well as tumor formation and metastasis in xenograft mice. The underlying molecular mechanisms leading to metastasis were also examined.ResultsIt was found that overexpression of UEV1A alone, but not UEV1C or MMS2, is sufficient to induce cell invasion in vitro and metastasis in vivo. This process is mediated by NF-κB activation and requires functional Ubc13. Our experimental data establish that among NF-κB target genes, UEV1A-regulated matrix metalloproteinase-1 (MMP1) expression plays a critical role in cell invasion and metastasis. Interestingly, experimental depletion of UEV1 in MDA-MB-231 cells reduces MMP1 expression and prevents tumor formation and metastasis in a xenograft mouse model, while overexpression of MMP1 overrides the metastasis effects in UEV1-depleted cells.ConclusionsThese results identify UEV1A as a potential therapeutic target in the treatment of metastasic breast cancers.

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“…As mentioned above, K1 antagonizes type I IFN (13) and NF-B (8, 9). Interestingly, genes encoding a type I IFN (Ifnb) or NF-B-controlled genes (Nfkbia and Tnf) (50)(51)(52)(53) showed no K1L-dependent change in expression. However, other genes at least partially controlled by NF-B (Ifna4, Il7, and Nfkb2) showed significant downregulation in the absence of K1L (54,55).…”

Section: Figmentioning

confidence: 99%

Deletion of the K1L Gene Results in a Vaccinia Virus That Is Less Pathogenic Due to Muted Innate Immune Responses, yet Still Elicits Protective Immunity

Cruz

Han

Roy

et al. 2017

J Virol

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All viruses strategically alter the antiviral immune response to their benefit. The vaccinia virus (VACV) K1 protein has multiple immunomodulatory effects in tissue culture models of infection, including NF-B antagonism. However, the effect of K1 during animal infection is poorly understood. We determined that a K1L-less vaccinia virus (vΔK1L) was less pathogenic than wild-type VACV in intranasal and intradermal models of infection. Decreased pathogenicity was correlated with diminished virus replication in intranasally infected mice. However, in intradermally inoculated ears, vΔK1L replicated to levels nearly identical to those of VACV, implying that the decreased immune response to vΔK1L infection, not virus replication, dictated lesion size. Several lines of evidence support this theory. First, vΔK1L induced slightly less edema than vK1L, as revealed by histopathology and noninvasive quantitative ultrasound technology (QUS). Second, infiltrating immune cell populations were decreased in vΔK1L-infected ears. Third, cytokine and chemokine gene expression was decreased in vΔK1L-infected ears. While these results identified the biological basis for smaller lesions, they remained puzzling; because K1 antagonizes NF-B in vitro, antiviral gene expression was expected to be higher during vΔK1L infection. Despite these diminished innate immune responses, vΔK1L vaccination induced a protective VACV-specific CD8 ϩ T cell response and protected against a lethal VACV challenge. Thus, vΔK1L is the first vaccinia virus construct reported that caused a muted innate immune gene expression profile and decreased immune cell infiltration in an intradermal model of infection yet still elicited protective immunity. IMPORTANCE The vaccinia virus (VACV) K1 protein inhibits NF-B activation among its other antagonistic functions.A virus lacking K1 (vΔK1L) was predicted to be less pathogenic because it would trigger a more robust antiviral immune response than VACV. Indeed, vΔK1L was less pathogenic in intradermally infected mouse ear pinnae. However, vΔK1L infection unexpectedly elicited dramatically reduced infiltration of innate immune cells into ears. This was likely due to decreased expression of cytokine and chemokine genes in vΔK1L-infected ears. As such, our finding contradicted observations from cell culture systems. Interestingly, vΔK1L conferred protective immunity against lethal VACV challenge. This suggests that the muted immune response triggered during vΔK1L infection remained sufficient to mount an effective protective response. Our results highlight the complexity and unpredictable nature of virus-host interactions, a relationship that must be understood to better comprehend virus pathogenesis or to manipulate viruses for use as vaccines.

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Structural analysis of the rabbit TNF locus, containing the genes encoding TNF-β(lymphotoxin) and TNF-α(tumor necrosis factor)

Cited by 39 publications

References 31 publications

Complex NF-κB Interactions at the Distal Tumor Necrosis Factor Promoter Region in Human Monocytes

Complex NF-κB Interactions at the Distal Tumor Necrosis Factor Promoter Region in Human Monocytes

Ubiquitin-conjugating enzyme complex Uev1A-Ubc13 promotes breast cancer metastasis through nuclear factor-кB mediated matrix metalloproteinase-1 gene regulation

Deletion of the K1L Gene Results in a Vaccinia Virus That Is Less Pathogenic Due to Muted Innate Immune Responses, yet Still Elicits Protective Immunity

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