Molecular control of tissue‐specific expression at the mouse TNF locus

Jongeneel, C. Victor; Shakhov, Alexander N.; Nedospasov, Sergei A.; Cerottini, Jean‐Charles

doi:10.1002/eji.1830190321

Cited by 32 publications

(24 citation statements)

References 25 publications

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“…1. These constructs were designed to include either the major portion of the mouse TNF promoter (containing all of the NF-KB elements important for gene induction in macrophages) (8,9) or a markedly truncated version of the promoter (containing only an SP-1 element and a "TATA" box). Since they were prepared at different times and in different laboratories, minor discrepancies in promoter length (1059 bp, 1009 bp, or 939 bp for the long form and 109 bp or 100 bp for the short form) are apparent in Fig.…”

Section: Methodsmentioning

confidence: 99%

Constitutive activity of the tumor necrosis factor promoter is canceled by the 3' untranslated region in nonmacrophage cell lines; a trans-dominant factor overcomes this suppressive effect.

Kruys

Kemmer

Shakhov³

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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Constitutive activity of the tumor necrosis factor promoter is canceled by the 3' untranslated region in nonmacrophage cell lines; a trans-dominant factor overcomes this suppressive effect ( ABSTRACTThe role of the mouse tumor necrosis factor (TNF) promoter, 5' untranslated region (UTR), and 3' UTR in TNF gene expression has been examined in three nonmacrophage cell lines (HeLa, NIH 3T3,. The TNF promoter is not macrophage-specific. On the contrary, it constitutively drives reporter gene expression in all three cell lines. Not only the full-length promoter but also truncated versions of the promoter, lacking NF-icB binding motifs, are

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Section: Methodsmentioning

confidence: 99%

Constitutive activity of the tumor necrosis factor promoter is canceled by the 3' untranslated region in nonmacrophage cell lines; a trans-dominant factor overcomes this suppressive effect.

Kruys

Kemmer

Shakhov³

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

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“…The pleiotropic nature of TNF␣ has led to evolution of stringent and redundant regulatory mechanisms. These mechanisms target distinct processes required for TNF␣ gene expression, including (i) transcription initiation (6,7), (ii) transcript elongation (8), (iii) mRNA stabilization (7,9,10), and (iv) translation (11,12). We recently reported that the translational efficiency of TNF␣ transcripts may be regulated through changes in the length of the 3Ј poly(A) tail and the efficiency of ribosome recruitment (13).…”

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confidence: 99%

Inhibition of Tumor Necrosis Factor-α Transcription in Macrophages Exposed to Febrile Range Temperature

Singh¹,

Viscardi²,

Kalvakolanu³

et al. 2000

Journal of Biological Chemistry

113

105

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We previously reported that expression of tumor necrosis factor-␣ (TNF␣) was attenuated in macrophages exposed to febrile range temperatures. In this study, we analyzed the influence of temperature on TNF␣ transcription in the Raw 264.7 macrophage cell line during incubation at 37 and 39.5°C. The initial activation of TNF␣ transcription in response to endotoxin (LPS) was comparable in the 37 and 39.5°C cell cultures, peaking within 10 min of LPS stimulation. However, the duration of transcriptional activation was markedly reduced in the 39.5°C cells (30 -60 min) compared with the 37°C cells (2-4 h). Deletion mapping of the TNF␣ gene revealed that the proximal 85-nucleotide promoter sequence and the 5-untranslated region were sufficient for temperature sensitivity. This sequence contains six heat shock response element (HRE) half-sites but no complete HREs. Electrophoretic mobility shift and immunoblot assays demonstrated that nuclear transclocation of heat shock factor (HSF) and its activation to a DNA-binding form occurred in the 39.5°C cells in the absence of heat shock protein-70 gene activation. The proximal TNF␣ promoter/5-untranslated region sequence competed for HSF binding to a classic HRE. Overexpression of HSF-1 reduced activity of the TNF␣ promoter. These data suggest that partial activation of HSF-1 during exposure to febrile, sub-heat shock temperatures may block TNF␣ transcription by binding to its proximal promoter or 5-untranslated region. Tumor necrosis factor-␣ (TNF␣)1 is an early pivotal mediator expressed in response to infection and injury (1). While TNF␣ is essential for optimal host defense (2, 3), persistent or inappropriately high TNF␣ expression has grave consequences, including multiorgan failure and death (4, 5). The pleiotropic nature of TNF␣ has led to evolution of stringent and redundant regulatory mechanisms. These mechanisms target distinct processes required for TNF␣ gene expression, including (i) transcription initiation (6, 7), (ii) transcript elongation (8), (iii) mRNA stabilization (7, 9, 10), and (iv) translation (11, 12). We recently reported that the translational efficiency of TNF␣ transcripts may be regulated through changes in the length of the 3Ј poly(A) tail and the efficiency of ribosome recruitment (13).Several soluble mediators that are induced by TNF␣ are negative regulators of further TNF␣ expression, including prostaglandin E 2 (14), glucocorticoids (15), interleukin (IL)-4 (16), IL-6 (17), IL-10 (18), , and transforming growth factor-␤ (20). We reported that exposing macrophages to febrile range temperatures inhibited TNF␣ expression as potently as these soluble inhibitors (10, 21), demonstrating that a physical factor can also act as an endogenous regulator of biological processes. In Raw 264.7 macrophages stimulated with bacterial endotoxin (LPS), TNF␣ mRNA accumulation and TNF␣ secretion were attenuated during culture at 40°C as compared with 37°C cell cultures (10). We reported that TNF␣ mRNA was destabilized in the warmer cells (10), but the extent of tra...

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“…Given the core region homology between the TNFRE and NF-KB motifs (one of seven differences), the binding of an NF-KB-like factor is not surprising. The NF-KB2b site (GGGGCTGCCCC) in the TNF promoter is closely homologous to the TNFRE (20). NF-KB has only weak affinity for this motif, indicating that it is readily displaced.…”

Section: Methodsmentioning

confidence: 99%

“…TNF-stimulated upregulation of many genes, including cytokines, cytokine receptors, immunoglobulins, major histocompatibility antigens, and modulation of human immunodeficiency virus 1 replication, involves induction of the nuclear transcription factor KB (NF-KB) (9,13,19,20,27,34,36,39). TNF receptor binding results in the phosphorylation and subsequent dissociation of the inhibitor IKB from cytoplasmic NF-KB, freeing NF-KB to bind to specific enhancer sites on DNA (2,39,47).…”

mentioning

confidence: 99%

Characterization of a tumor necrosis factor-responsive element which down-regulates the human osteocalcin gene.

Li¹,

Stashenko²

1993

Mol. Cell. Biol.

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Tumor necrosis factor (TNF) down-regulates the production of bone matrix proteins by osteoblasts, thereby inhibiting bone formation. Osteocalcin, the major noncollagenous protein in bone, is inhibited by TNF at the transcriptional level. Mapping studies were undertaken to characterize the TNF-responsive element (TNFRE) in the osteocalcin promoter. Deletion analysis localized the TNFRE to the -522/-511 region, which contains a 9-bp palindromic motif (AGGCTGCCT). Promoter segments containing this sequence down-regulated a heterologous simian virus 40 promoter. Site-specific mutagenesis of the TNFRE eliminated TNF downregulation. Mobility shift assays demonstrated that a constitutively expressed nuclear factor bound to the TNFRE; this factor was tentatively identified as the p50 homodimer of NF-KB. TNF stimulation induced a second TNFRE-binding protein which displaced the constitutive factor. The TNF-induced protein was not inhibitable by the NF-KB consensus sequence and was unreactive with anti-NF-cB antiserum. DNase footprinting demonstrated that both factors protected the -522/-501 portion of the promoter, consistent with the results of mapping studies and competitive mobility shift assays. It is hypothesized that the generalized catabolic activities of TNF in infectious and malignant diseases may be regulated via this novel element.Tumor necrosis factor (TNF) is a highly pleiotropic cytokine which induces many proinflammatory effects, including fever, shock, cytokine and prostaglandin synthesis, and bone and cartilage resorption (3, 4). TNF-stimulated upregulation of many genes, including cytokines, cytokine receptors, immunoglobulins, major histocompatibility antigens, and modulation of human immunodeficiency virus 1 replication, involves induction of the nuclear transcription factor KB (NF-KB) (9,13,19,20,27,34,36,39). TNF receptor binding results in the phosphorylation and subsequent dissociation of the inhibitor IKB from cytoplasmic NF-KB, freeing NF-KB to bind to specific enhancer sites on DNA (2,39,47).TNF also has significant inhibitory effects on the expression of other genes. TNF plays a key role in the cachexia (wasting) secondary to malignancy, extensive burns, and chronic infections, including AIDS (28,33,43). Cachexia involves the consumption of whole-body lipid reserves, a consequence of the down-regulation of lipoprotein lipase and other lipogenic enzymes (5), as well as the decreased synthesis of many structural proteins of muscle and bone, including actin, myosin, collagen, and osteocalcin (3, 15). In contrast to inductive phenomena, the mechanism(s) by which TNF negatively regulates these various proteins has not yet been elucidated.Osteocalcin is an osteoblast-specific polypeptide which constitutes the major noncollagenous bone matrix protein (18). Osteocalcin production correlates with histomorphometric parameters of bone formation, and levels of this protein in serum have been used clinically to evaluate whole-body bone formation rates (11). Osteocalcin has therefore been widely used as ...

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Molecular control of tissue‐specific expression at the mouse TNF locus

Cited by 32 publications

References 25 publications

Constitutive activity of the tumor necrosis factor promoter is canceled by the 3' untranslated region in nonmacrophage cell lines; a trans-dominant factor overcomes this suppressive effect.

Constitutive activity of the tumor necrosis factor promoter is canceled by the 3' untranslated region in nonmacrophage cell lines; a trans-dominant factor overcomes this suppressive effect.

Inhibition of Tumor Necrosis Factor-α Transcription in Macrophages Exposed to Febrile Range Temperature

Characterization of a tumor necrosis factor-responsive element which down-regulates the human osteocalcin gene.

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