Myokai F, Takashiba S, Lebo R, Amar S.. A novel lipopolysaccharide-induced transcription factor regulating tumor necrosis factor alpha gene expression: molecular cloning, sequencing, characterization, and chromosomal assignment. Proc Natl Acad Sci USA 96: 4518-4523

Boston University, Department of Periodontology and Oral Biology, School of Dental Medicine, Boston, MA 02118, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/1999; 96(8):4518-23. DOI: 10.1073/pnas.96.8.4518
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Lipopolysaccharide (LPS) is a potent stimulator of monocytes and macrophages, causing secretion of tumor necrosis factor alpha (TNF-alpha) and other inflammatory mediators. Given the deleterious effects to the host of TNF-alpha, it has been postulated that TNF-alpha gene expression must be tightly regulated. The nature of the nuclear factor(s) that control TNF-alpha gene transcription in humans remains obscure, although NF-kappaB has been suggested. Our previous studies pertaining to macrophage response to LPS identified a novel DNA-binding domain located from -550 to -487 in the human TNF-alpha promoter that contains transcriptional activity, but lacks any known NF-kappaB-binding sites. We have used this DNA fragment to isolate and purify a 60-kDa protein binding to this fragment and obtained its amino-terminal sequence, which was used to design degenerate probes to screen a cDNA library from THP-1 cells. A novel cDNA clone (1.8 kb) was isolated and fully sequenced. Characterization of this cDNA clone revealed that its induction was dependent on LPS activation of THP-1 cells; hence, the name LPS-induced TNF-alpha factor (LITAF). Inhibition of LITAF mRNA expression in THP-1 cells resulted in a reduction of TNF-alpha transcripts. In addition, high level of expression of LITAF mRNA was observed predominantly in the placenta, peripheral blood leukocytes, lymph nodes, and the spleen. Finally, chromosomal localization using fluorescence in situ hybridization revealed that LITAF mapped to chromosome 16p12-16p13.3. Together, these findings suggest that LITAF plays an important role in the activation of the human TNF-alpha gene and proposes a new mechanism to control TNF-alpha gene expression.

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    • "In this study, by integrating expression analysis of human B-lymphocyte subsets, ChIP assays and dual luciferase experiments , we demonstrated transcriptional repression of LITAF by BCL6 in B cells, suggesting that LITAF may play a role in mature B-cell development. Despite the fact that LITAF induces TNF gene expression and secretion upon LPS stimulation in monocytes (Myokai et al, 1999; Tang et al, 2005, 2006), we found that LITAF was rarely induced by LPS in B-cell lymphoma cells and TNF secretion was not associated with LITAF expression. Furthermore, the location of LITAF in cytoplasmic vesicles observed by IF, as well as its absence from the nucleus of B cells assessed by IHC and "
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    ABSTRACT: We have previously reported that LITAF is silenced by promoter hypermethylation in germinal centre-derived B-cell lymphomas, but beyond these data the regulation and function of lipopolysaccharide-induced tumour necrosis factor (TNF) factor (LITAF) in B cells are unknown. Gene expression and immunohistochemical studies revealed that LITAF and BCL6 show opposite expression in tonsil B-cell subpopulations and B-cell lymphomas, suggesting that BCL6 may regulate LITAF expression. Accordingly, BCL6 silencing increased LITAF expression, and chromatin immunoprecipitation and luciferase reporter assays demonstrated a direct transcriptional repression of LITAF by BCL6. Gain- and loss-of-function experiments in different B-cell lymphoma cell lines revealed that, in contrast to its function in monocytes, LITAF does not induce lipopolysaccharide-mediated TNF secretion in B cells. However, gene expression microarrays defined a LITAF-related transcriptional signature containing genes regulating autophagy, including MAP1LC3B (LC3B). In addition, immunofluorescence analysis co-localized LITAF with autophagosomes, further suggesting a possible role in autophagy modulation. Accordingly, ectopic LITAF expression in B-cell lymphoma cells enhanced autophagy responses to starvation, which were impaired upon LITAF silencing. Our results indicate that the BCL6-mediated transcriptional repression of LITAF may inhibit autophagy in B cells during the germinal centre reaction, and suggest that the constitutive repression of autophagy responses in BCL6-driven lymphomas may contribute to lymphomagenesis.
    British Journal of Haematology 06/2013; 162(5). DOI:10.1111/bjh.12440 · 4.71 Impact Factor
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    • "British Journal of Pharmacology (2013) 169 1672–1692 1673 T-cell transcription factor (NFAT) (McCaffrey et al., 1994; Tsai et al., 1996a,b), NF-kB (Udalova et al., 1998; Kuprash et al., 1999), early growth response protein-1 (Kramer et al., 1994), cAMP response element binding protein (CREB) (Geist et al., 1997), CCAAT/enhancer binding protein b (C/EBPb) (Pope et al., 1994; Wedel et al., 1996; Zagariya et al., 1998), NF-E2- related factor 1 (Novotny et al., 1998; Prieschl et al., 1998) and LPS-induced TNF-a factor (LITAF) (Takashiba et al., 1995; Myokai et al., 1999) (Figure 1). Hence, different transcription factors appear to be involved in the stimulation of TNF expression by various stimuli and in different cell types. "
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    ABSTRACT: Unlabelled: TNFs are major mediators of inflammation and inflammation-related diseases, hence, the United States Food and Drug Administration (FDA) has approved the use of blockers of the cytokine, TNF-α, for the treatment of osteoarthritis, inflammatory bowel disease, psoriasis and ankylosis. These drugs include the chimeric TNF antibody (infliximab), humanized TNF-α antibody (Humira) and soluble TNF receptor-II (Enbrel) and are associated with a total cumulative market value of more than $20 billion a year. As well as being expensive ($15 000-20 000 per person per year), these drugs have to be injected and have enough adverse effects to be given a black label warning by the FDA. In the current report, we describe an alternative, curcumin (diferuloylmethane), a component of turmeric (Curcuma longa) that is very inexpensive, orally bioavailable and highly safe in humans, yet can block TNF-α action and production in in vitro models, in animal models and in humans. In addition, we provide evidence for curcumin's activities against all of the diseases for which TNF blockers are currently being used. Mechanisms by which curcumin inhibits the production and the cell signalling pathways activated by this cytokine are also discussed. With health-care costs and safety being major issues today, this golden spice may help provide the solution. Linked articles: This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit
    British Journal of Pharmacology 02/2013; 169(8). DOI:10.1111/bph.12131 · 4.84 Impact Factor
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    • "The biological function of lipopolysaccharide-induced TNF factor (LITAF) is not well understood . It was originally cloned as a transcription factor modulating the tumor necrosis factor-α (TNF α) gene (Polyak et al., 1997; Myokai et al., 1999), but it has also been found to encode a lysosomal protein (Moriwaki et al., 2001). Litaf has not been investigated regarding potential function in cortical development. "
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    ABSTRACT: Whether induction of low-level neurogenesis in normally non-neurogenic regions of the adult brain mimics aspects of developmental neurogenesis is currently unknown. Previously, we and others identified that biophysically induced, neuron subtype-specific apoptosis in mouse neocortex results in induction of neurogenesis of limited numbers of subtype-appropriate projection neurons with axonal projections to either thalamus or spinal cord, depending on the neuron subtype activated to undergo targeted apoptosis. Here, we test the hypothesis that developmental genes from embryonic corticogenesis are re-activated, and that some of these genes might underlie induction of low-level adult neocortical neurogenesis. We directly investigated this hypothesis via microarray analysis of microdissected regions of young adult mouse neocortex undergoing biophysically activated targeted apoptosis of neocortical callosal projection neurons. We compared the microarray results identifying differentially expressed genes with public databases of embryonic developmental genes. We find that, following activation of subtype-specific neuronal apoptosis, three distinct sets of normal developmental genes are selectively re-expressed in neocortical regions of induced neurogenesis in young adult mice: (1) genes expressed by subsets of progenitors and immature neurons in the developing ventricular and/or subventricular zones; (2) genes normally expressed by developmental radial glial progenitors; and (3) genes involved in synaptogenesis. Together with previous results, the data indicate that at least some developmental molecular controls over embryonic neurogenesis can be re-activated in the setting of induction of neurogenesis in the young adult neocortex, and suggest that some of these activate and initiate adult neuronal differentiation from endogenous progenitor populations. Understanding molecular mechanisms contributing to induced adult neurogenesis might enable directed CNS repair.
    Frontiers in Neuroscience 02/2012; 6:12. DOI:10.3389/fnins.2012.00012 · 3.66 Impact Factor
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