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
Source: PubMed


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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    • "Lipopolysaccharide-induced TNFa factor (LITAF) appears to be a multifunctional small protein consisting of 161 amino acids[17]. It has been characterized as a transcription factor for inflammatory cytokines in macrophages[18]. In response to LPS, LITAF translocates into the nucleus and binds to a specific element on promoters for proinflammatory cytokines such as the TNFa promoter, where it interacts and cooperates with STAT6(B) to activate their transcription[19]. "
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    ABSTRACT: Bmi-1 is a transcriptional regulator that promotes tumor cell self-renewal and epithelial to mesenchymal transition and its upregulation is associated with tumor progression, AMPK is an intracellular fuel-sensing enzyme and plays important roles in tumor cell growth and progression. Thus, the present study aims to examine the regulation of Bmi-1 by AMPK. First, our data revealed that, as compared to adjacent normal tissue, Bmi-1 was highly expressed in gastric cancer, whereas phosphorylation of AMPK (p-AMPK) was reduced. Similar findings were observed in lung adenocarcinomas and appeared that the expression of Bmi-1 was correlated with pathological grades of the cancer, where opposite changes were found in p-AMPK. Second, Metformin, a pharmacological AMPK activator and anti-diabetic drug, or ectopic expression of LKB1, diminished expression of Bmi-1 in cancer cells, an event that was reversed by silencing LKB1. Third, knockdown of LITAF, previously identified as a downstream target of AMPK, upregulated Bmi-1, associated with increased cell viability, colony formation, and migration of cancer cells in vitro. Fourth, metformin increased the abundance of miR-15a, miR-128, miR-192, and miR-194, which was prevented by knockdown of LITAF. Accordingly, transfection of these individual miRNAs downregulated Bmi-1. Altogether, our data for the first time suggest a regulatory axis in cancer cells: AMPK upregulates LITAF, which in turn increases miRNAs, leading to attenuation of Bmi-1 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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    • "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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