A Fos protein containing the Jun leucine zipper forms a homodimer which binds to the AP1 binding site

Neuberg, Manfred; Adamkiewicz, Jürgen; Hunter, John B.; Müller, Rolf

doi:10.1038/341243a0

Cited by 70 publications

(43 citation statements)

References 19 publications

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“…The potent inflammation-related cis-activating transcription factors AP1 (16,17) and 19), as well as and matrix metalloproteinase-1 and -9 gene expression (21), are also strongly induced by the inflammatory mediator plateletactivating factor (PAF;. Although several synthetic GCs have been intensively studied at the gene signaling level (1-12) the molecular specificity and potency of the nonfluorinated GC budesonide epimer R (BUDeR) remains incompletely characterized.…”

Section: Introductionmentioning

confidence: 99%

Budesonide epimer R or dexamethasone selectively inhibit platelet-activating factor-induced or interleukin 1β-induced DNA binding activity ofcis-acting transcription factors and cyclooxygenase-2 gene expression in human epidermal keratinocytes

Lukiw¹,

Peláez²,

Martínez³

et al. 1998

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

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To further understand the molecular mechanism of glucocorticoid action on gene expression, DNA-binding activities of the cis-acting transcription factors activator protein 1 (AP1), AP2, Egr1 (zif268), NF-B, the signal transducers and activators of transcription proteins gamma interferon activation site (GAS), Sis-inducible element, and the TATA binding protein transcription factor II D (TFIID) were examined in human epidermal keratinocytes. The cytokine interleukin 1␤ (IL-1␤) and platelet-activating factor (PAF), both potent mediators of inflammation, were used as triggers for gene expression. Budesonide epimer R (BUDeR) and dexamethasone (DEX) were studied as potential antagonists. BUDeR or DEX before IL-1␤-or PAF-mediated gene induction elicited strong inhibition of AP1-, GAS-, and in particular NF-B-DNA binding (P < 0.001, ANOVA). Only small effects were noted on AP2, Egr1 (zif268), and Sis-inducible element-DNA binding (P > 0.05). No significant effect was noted on the basal transcription factor TFIID recognition of TATA-containing core promoter sequences (P > 0.68). To test the hypothesis that changing cis-acting transcription factor binding activity may be involved in inflammatoryresponse related gene transcription, RNA message abundance for human cyclooxygenase (COX)-1 and -2 (E.C.1.14.99.1) was assessed in parallel by using reverse transcription-PCR. Although the COX-1 gene was found to be expressed at constitutively low levels, the TATA-containing COX-2 gene, which contains AP1-like, GAS, and NF-B DNA-binding sites in its immediate promoter, was found to be strongly induced by IL-1␤ or PAF (P < 0.001). BUDeR and DEX both suppressed COX-2 RNA message generation; however, no correlation was associated with TFIID-DNA binding. These results suggest that on stimulation by mediators of inflammation, although the basal transcription machinery remains intact, modulation of cis-activating transcription factor AP1, GAS, and NF-B-DNA binding by the glucocorticoids BUDeR and DEX play important regulatory roles in the extent of specific promoter activation and hence the expression of key genes involved in the inflammatory response.Glucocorticosteroids (GCs) have long been used therapeutically as immunosuppressive and anti-inflammatory agents; however, the mechanism of their activity is only recently becoming understood at the genetic level. GCs interact with an intracellular GC receptor, which subsequently translocates to the nucleus as a ligand-activated transcriptional modulator. In turn, the GC receptor regulates the expression of genes such as those encoding cytokines, matrix metalloproteinases, and cell adhesion molecules known to be critical to both inflammation and the immune response (1, 2). Besides a direct "type 1" interaction with a palindromic GC responsive element in GC-sensitive gene promoters (3, 4), functions of the GC receptor also include a "type 2" interaction with chromatin-associated cis-acting transcription factors. For example, the GC receptor can physically interact with the Fos and J...

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Section: Introductionmentioning

confidence: 99%

Budesonide epimer R or dexamethasone selectively inhibit platelet-activating factor-induced or interleukin 1β-induced DNA binding activity ofcis-acting transcription factors and cyclooxygenase-2 gene expression in human epidermal keratinocytes

Lukiw¹,

Peláez²,

Martínez³

et al. 1998

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

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“…The Box VI extends from nucleotide -497 to -471 (Figure 2g), which shows homology with UPE region. Box IV corresponds to potential AP-1 site (Figure 2e) (Neuberg et al, 1989). In these two consensus sequences, UPE and AP-l draw a special attention.…”

Section: Resultsmentioning

confidence: 99%

“…A putative UPE consensus sequence (Magnuson and Jetton, 1993) at -497 to -471, AP-l site (Neuberg et al, 1989) at -373 to -357, HNF-5 at -118 to -105, C/EBP (Landschulz et al, 1988) at -273 to -266, Sp1 site (Biggs et al , 1988) at -239 to -230, andCAAT box (Mitchell andTjian, 1988) at -81 to -84 were observed. In vitro EMSA and DNase I footprinting revealed 6 protected regions.…”

Section: Discussionmentioning

confidence: 99%

A mechanism of differential expression of GLUT2 in hepatocyte and pancreatic β-cell line

Kim

Kim²,

Ahn³

1998

Exp Mol Med

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DNase I footprinting assay using liver nuclear extracts revealed six protected regions between nucleotide -600 and +110 and hence named Box I~VI. Upstream promoter element (UPE), a DNA element playing crucial role in transcriptional control of the tissue specific expression of pancreaticcell, has been detected within the proximal region of rat GLUT2 promoter. This region is included in Box VI. The protein-DNA interaction in this region (Box VI) was confirmed by mobility shift assay using liver nuclear extracts. Deletion of the region between -585 bp and -146 bp resulted in dramatic changes in promoter activity when they were expressed in liver and -cell derived cell line. When -585/-l46 construct was expressed in l i v e r, the activity was decreased to 46%, whereas the activity in -cell line, HIT-T15 cell, was increased by 84% when compared to -146/+190 construct. These opposing phenomena can be explained by the fact that -cell specifically expresses the UPE binding protein. Assuming that there may be Box VI-binding protein playing negative roles both in hepatocyte and -cell, and that the protein acts as a negative regulator of GLUT2 gene, the UPE binding protein in the -cell may overcome the inhibition by binding to the protein.K e y w o r d s : GLUT2 gene expression, hepatocyte, β-c e l l , upstream promoter element lntroduction Glucose uptake into mammalian cells is mediated by a family of glucose transporters (Takeda et al., 1993). In hepatocytes, pancreatic β-cells, and absorptive epithelial cells of the intestinal mucosa and kidney, the GLUT2 glucose transporter isoform is mainly responsible for glucose entry (Fukumoto et al., 1988). It has been shown that the GLUT2 gene expression is regulated differently in hepatocytes and β-cell, especially in diabetic states; the β-cell showed a marked reduction (up to 90%) in GLUT2 expression whereas GLUT2 expression in liver or kidney was unaltered (Thorens et al., l990). The regulation of GLUT2 gene expression has been studied in vitro by cell culture and in a number of animal models, showing an imbalanced glucose homeostasis (Asano et al., 1992;Postic et al., 1993). Generally, in diabetic status, it is accepted that there is a strong reduction in GLUT2 expression which is restricted to the pancreatic β-c e l l s while its expression in liver, pancreas, or kidney is unaltered or slightly increased Thorens et al., 1990;Ohneda et al. , 1993). The basic changes responsible for GLUT2 downregulation is not known. A study in which hyperglycemia was controlled to normoglycemic state in Zucker diabetic rats showed the gradual decrease in GLUT2 expression . It is suggested that in vitro glucose may directly stimulate GLUT2 gene expression while hyperglycemia in vivo causes a decreased GLUT2 expression in β-cell. To better understand the differential gene expression of GLUT2 between liver and β-cell, we have cloned the promoter region of GLUT2 along with complete intron-exon relationship (Ahn et al., 1996).The aim of this study was to analyze rat GLUT2 promoter eleme...

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“…The theoretically encoded CG30 polypeptide was shown to contain a number of sequence motifs that are characteristic of proteins functioning as transcription factors. These included a RING finger-like, putative DNA-binding domain (Chen et al, 1992;Everett, i988;Lovering et al, 1993;Moriuchi et al, 1994;Tagawa et al, 1990); a leucine zipper/basic region of a presumed protein dimerization and DNA-binding function (Johnson & McKnight, 1989;Neuberg et al, 1989;Nakabeppu & Nathans, 1989;Turner & Tjian, 1989); and an acidic domain reminiscent of a transcription factor trans-activation domain (Abate et al, 1991;Mitchell & Tjian, 1989).…”

Section: Introductionmentioning

confidence: 99%

The genes encoding the P39 and CG30 proteins of Bombyx mori nuclear polyhedrosis virus

Iatrou

1996

Journal of General Virology

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A Fos protein containing the Jun leucine zipper forms a homodimer which binds to the AP1 binding site

Cited by 70 publications

References 19 publications

Budesonide epimer R or dexamethasone selectively inhibit platelet-activating factor-induced or interleukin 1β-induced DNA binding activity ofcis-acting transcription factors and cyclooxygenase-2 gene expression in human epidermal keratinocytes

Budesonide epimer R or dexamethasone selectively inhibit platelet-activating factor-induced or interleukin 1β-induced DNA binding activity ofcis-acting transcription factors and cyclooxygenase-2 gene expression in human epidermal keratinocytes

A mechanism of differential expression of GLUT2 in hepatocyte and pancreatic β-cell line

The genes encoding the P39 and CG30 proteins of Bombyx mori nuclear polyhedrosis virus

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