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Query: UNIPROT:P06889 (Mol)
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Transthyretin (TTR) and alpha 1-antitrypsin (alpha 1-AT) are expressed at high levels in the liver and also in at least one other cell type. We report here a detailed analysis of the proximal regulatory region of the TTR gene, which has uncovered two new DNA-binding factors that are present mainly (or only) in hepatocytes. One of these new factors, hepatocyte nuclear factor 3 (HNF-3), binds to two sites that are crucial in TTR expression as well as to two additional sites in the alpha 1-AT proximal enhancer region. The second new factor, HNF-4, binds to two sites in TTR that are required for gene activity. We had previously identified binding sites for another hepatocyte-enriched DNA-binding protein (C/EBP or a relative thereof), and additional promoter-proximal sites for that protein in both TTR and alpha 1-AT are also reported here. From these results it seems clear that cell-specific expression is not simply the result of a single cell-specific factor for each gene but the result of a combination of such factors. The variation and distribution of such factors among different cell types could be an important basis for the coordinate expression of the TTR and alpha 1-AT genes in the liver or the discordant transcriptional activation of these genes in a few other cell types. The identification of such cell-enriched factors is a necessary prelude to understanding the basis for cell specificity.
Mol Cell Biol 1989 Apr
PMID:Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes. 278 40

We describe the purification to apparent homogeneity of the murine immunoglobulin heavy-chain (IgH) enhancer-binding protein mu EBP-E from murine plasmacytoma cells by ion exchange and affinity chromatography. Glycerol gradient sedimentation, UV cross-linking, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis confirm that mu EBP-E is a 45-kilodalton molecular mass protein. Orthophenanthroline-copper chemical nuclease footprinting with purified protein has identified high-affinity binding sites for mu EBP-E within the IgH enhancer at the previously identified site E and at sites within IgH promoters and in the kappa light-chain enhancer. Equilibrium binding studies indicate that the dissociation constants for mu EBP-E binding to site E within the enhancer and to a binding site within the V1 heavy-chain promoter are quite low, about 2 x 10(-11) M. Comparison of four mu EBP-E recognition sequences detects only limited sequence similarity among binding sites.
Mol Cell Biol 1988 Nov
PMID:Purified mu EBP-E binds to immunoglobulin enhancers and promoters. 314 4

We previously demonstrated that down-regulation of protein kinase C (PKC) by prolonged 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment leads to the specific repression of GnRH transcription in GT1-7 hypothalamic neurons. Here we have investigated the regulatory sequences and cognate DNA-binding proteins that mediate this transcriptional response. The promoter-proximal section of the GnRH gene contains an evolutionarily conserved sequence that is bound along its entire length by GT1-7 nuclear proteins in DNase I protection assays. Two distinct regions within this sequence are required for PKC regulation of the GnRH gene, as excision of either region results in loss of TPA repression of transcription. Excision of either of these regions also decreases basal transcription, demonstrating their role in GnRH promoter function. One region encompasses three AT-rich protein-binding sites; the other is an extended region of continuous DNase I protection, 50 nucleotides in length, that contains consensus recognition motifs for the CCAAT/EBP and helix-loop-helix families of transcription factors. Mobility shift analysis of binding to the latter region reveals that TPA treatment of GT1-7 neurons induces the formation of a specific DNA-protein complex with kinetics of appearance consistent with a role in repression of GnRH transcription. Thus, the sequences that mediate PKC regulation of GnRH are proximal to the promoter, evolutionarily conserved, and form TPA-inducible complexes with GT1-7 nuclear proteins.
Mol Endocrinol 1995 Jul
PMID:Regulation of gonadotropin-releasing hormone transcription by protein kinase C is mediated by evolutionarily conserved promoter-proximal elements. 747 68

A highly conserved CCAAT/enhancer-binding protein (C/EBP)-binding site centered around -134 relative to the transcription start site in the rat beta-casein gene promoter is capable of interacting specifically with recombinant and mammary gland C/EBP proteins. Western blot analysis indicates that C/EBP levels change dramatically throughout mammary gland development. C/EBP alpha expression is barely detectable in mammary glands from virgin and pregnant animals but is expressed at high levels during lactation and at lower levels during involution. The expression of three C/EBP beta isoforms [the liver-enriched activating proteins (LAPs); and the liver-enriched inhibiting protein (LIP)] is elevated throughout pregnancy, with LIP expression increasing more than 100-fold. Thus, during pregnancy, a low LAP/LIP ratio (< 5) is maintained. C/EBP beta expression decreases at parturition, with LIP diminishing to levels observed in the virgin gland. Therefore, during lactation a more than 100-fold increase in the LAP/LIP ratio is observed. Treatment of the HC11 mammary epithelial cell line with hydrocortisone results in a 10- to 20-fold inhibition of LIP expression, with only minor changes in LAP levels. Therefore, glucocorticoids may impinge upon beta-casein gene expression by altering the ratio of the inhibitory to the activating isoforms of C/EBP beta. Several previously defined casein gene promoter regions capable of conferring hormone and extracellular matrix inducibility to reporter genes in mammary cells are suggested to be composite response elements, containing putative binding sites for the same set of hormonally and developmentally regulated factors: C/EBP, MGF/Stat5, and the glucocorticoid receptor.
Mol Endocrinol 1995 Sep
PMID:Developmentally and hormonally regulated CCAAT/enhancer-binding protein isoforms influence beta-casein gene expression. 749 Nov 14

Three regions required for the expression of a mouse major urinary protein (MUP) transgene were identified by a deletion analysis. One of these was located upstream of the cap site between -2139 and -1800, another was the proximal promoter region downstream of -324 and the third lay within the 338 nucleotide intron 1. Both the proximal promoter and intron 1 are involved in sexually dimorphic expression of the transgene (male/female ratio 20), which is dictated by the different temporal profiles of circulating GH in the two sexes. The data also indicated that the region between exons 3 and 7 may contribute to full expression in males and that a region between -718 and -324 may contribute towards the low expression level that obtains in females, but compared with the three principal regions the effects of these regions are relatively minor. We propose (1) that full expression of the transgene requires the co-operation of transcription factors bindings to the three principal regions and (2) that the difference in expression between the sexes relates to interactions between transcription factors bound to the proximal promoter and to sites in intron 1. Our results complement earlier in vitro footprinting and gel-retardation studies of the homologous rat apha 2u-globulin genes. These identified a number of response elements, including putative C/EBP and AP1 sites in the proximal promoter and intron 1 respectively and three putative psi NF-1 sites, two in the proximal promoter and one in intron 1, but proof of the functionality of these sites in regulating transcription was lacking. The proximal promoter also contained a 34 nucleotide sequence that has 70% identity with the SPI GH response element.
J Mol Endocrinol 1995 Feb
PMID:Localization of the response elements of a gene induced by intermittent growth hormone stimulation. 753 14

Gram-negative sepsis is the most common cause of the adult respiratory distress syndrome (ARDS). Lipopolysaccharide (LPS) when administered in vivo produces pathophysiologic changes similar to those seen in ARDS. The pathogenesis of these changes is mediated in part by oxidative stress. We demonstrate that LPS induces high mRNA levels of the stress-inducible gene heme oxygenase-1 (HO-1) in the rat lung. Increased HO-1 mRNA levels correlate with increased HO-1 protein and enzyme activity. Immunohistochemical analyses of lung tissues from rats treated with LPS reveal abundant HO-1 expression in inflammatory and bronchoalveolar epithelial cells. We further examined the molecular regulation of HO-1 gene expression after exposure of RAW 264.7 macrophage cells to LPS in vitro. These cells respond to LPS with increased HO-1 mRNA expression and HO-1 gene transcription. Transcriptional activation of the mouse HO-1 gene by LPS is mediated by a 5' distal enhancer fragment located approximately 4 kbp upstream from the transcription site. Electrophoretic mobility shift assays show increased activator protein-1 (AP-1) binding activity in RAW 264.7 cells after LPS treatment. Mutation of the AP-1 binding site in this enhancer fragment completely abolishes HO-1 gene activation while mutation of CCAAT/enhancer-binding protein (C/EBP) binding site exerts negligible effect, suggesting that the AP-1 family of transcription factors plays a critical role in regulating HO-1 gene activation following LPS treatment. Furthermore, upstream phosphorylation events modulate this AP-1-dependent expression of the HO-1 gene after LPS treatment.
Am J Respir Cell Mol Biol 1995 Oct
PMID:Induction of heme oxygenase-1 gene expression by lipopolysaccharide is mediated by AP-1 activation. 754 68

Growth factor receptors play an important role in hematopoiesis. In order to further understand the mechanisms directing the expression of these key regulators of hematopoiesis, we initiated a study investigating the transcription factors activating the expression of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor alpha gene. Here, we demonstrate that the human GM-CSF receptor alpha promoter directs reporter gene activity in a tissue-specific fashion in myelomonocytic cells, which correlates with its expression pattern as analyzed by reverse transcription PCR. The GM-CSF receptor alpha promoter contains an important functional site between positions -53 and -41 as identified by deletion analysis of reporter constructs. We show that the myeloid and B cell transcription factor PU.1 binds specifically to this site. Furthermore, we demonstrate that a CCAAT site located upstream of the PU.1 site between positions -70 and -54 is involved in positive-negative regulation of the GM-CSF receptor alpha promoter activity. C/EBP alpha is the major CCAAT/enhancer-binding protein (C/EBP) form binding to this site in nuclear extracts of U937 cells. Point mutations of either the PU.1 site or the C/EBP site that abolish the binding of the respective factors result in a significant decrease of GM-CSF receptor alpha promoter activity in myelomonocytic cells only. Furthermore, we demonstrate that in myeloid and B cell extracts, PU.1 forms a novel, specific, more slowly migrating complex (PU-SF) when binding the GM-CSF receptor alpha promoter PU.1 site. This is the first demonstration of a specific interaction with PU.1 on a myeloid PU.1 binding site. The novel complex is distinct from that described previously as binding to B cell enhancer sites and can be formed by addition of PU.1 to extracts from certain nonmyeloid cell types which do not express PU.1, including T cells and epithelial cells, but not from erythroid cells. Furthermore, we demonstrate that the PU-SF complex binds to PU.1 sites found on a number of myeloid promoters, and its formation requires an intact PU.1 site adjacent to a single-stranded region. Expression of PU.1 in nonmyeloid cells can activate the GM-CSF receptor alpha promoter. Deletion of the amino-terminal region of PU.1 results in a failure to form the PU-SF complex and in a concomitant loss of transactivation, suggesting that formation of the PU-SF complex is of functional importance for the activity of the GM-CSF receptor alpha promoter. Finally, we demonstrate that C/EBP alpha can also active the GM-CSF receptor alpha promoter in nonmyeloid cells. These results suggest that PU.1 and C/EBP alpha direct the cell-type-specific expression of GM-CSF receptor alpha, further establish the role of PU.1 as a key regulator of hematopoiesis, and point to C/EBP alpha as an additional important factor in this process.
Mol Cell Biol 1995 Oct
PMID:PU.1 (Spi-1) and C/EBP alpha regulate expression of the granulocyte-macrophage colony-stimulating factor receptor alpha gene. 756 36

Several transcription regulatory elements that interact with cellular DNA-binding proteins have been identified in the HIV-1 long terminal repeat (LTR). We have identified two sequence motifs in the U3 region of the LTR that are similar to the consensus 9-bp DNA-binding element of the CCAAT/enhancer-binding protein (C/EBP) family of transcription factors. One of the sequences (promoter-proximal) mapped immediately upstream of the NF-kappa B element, whereas the other (promoter-distal) completely overlapped the upstream stimulatory factor (USF) binding site. In this study, we investigated the role of the enhancer-proximal consensus C/EBP binding sequence in the expression of the HIV-1 LTR. In cotransfection assays we found that although this sequence is a functional C/EBP-responsive element, the regulation of the HIV promoter by C/EBP is very complex. C/EBP isoforms inhibited the phorbol 12-myristate 13-acetate (PMA)-stimulated HIV-1 promoter activity in human glioblastoma U138MG and neuroblastoma SHSY5Y cells, but not in HeLa epithelial cells, and this inhibition required the NF-kappa B element. C/EBP also downregulated the HIV NF-kappa B element-containing SV40 early promoter activity, regardless of the presence of the flanking C/EBP-binding sequences, in the two brain-derived cells. In electrophoretic mobility shift assays with nuclear extracts from HeLa and U138MG cells, purified C/EBP markedly increased the complex formation between endogenous proteins and the NF-kappa B DNA probe without detectable association with the complex. However, with extracts from U138MG cells but not from HeLa cells, a slow migrating complex was observed. Our data suggest that the C/EBP family of transcription factors can downregulate the HIV-1 promoter activity in CNS-derived cells through the NF-kappa B binding elements.
J Mol Neurosci
PMID:NF-kappa B site-mediated negative regulation of the HIV-1 promoter by CCAAT/enhancer binding proteins in brain-derived cells. 757 67

In this study, we have used the rat model of hyperoxia to examine the molecular responses to oxidative stress in lung. We show that in addition to the antioxidant enzyme manganese superoxide dismutase, expression of a variety of stress-responsive genes including heme oxygenase-1, c-fos, c-jun, CAAT-enhancer binding protein (C/EBP)-beta, and C/EBP-delta were increased after hyperoxia. Increased c-fos, c-jun, C/EBP-beta, and C/EBP-delta mRNA expression was correlated with increased DNA binding activity of the transcription factor complexes activator protein 1 and C/EBP in tissue lysates. Because oxidative damage plays an important role in the aging process and little is known about the susceptibility of aged rats to hyperoxia, we also examined the relative tolerance of old rats to hyperoxia. Surprisingly, we observed that aged rats exhibit greater tolerance to hyperoxic stress than young rats. Old rats exhibited decreased arterial oxygen tension when compared to young rats after hyperoxia exposure. This increased tolerance coincided with decreased albumin levels in bronchoalveolar lavage and the delayed onset of activation of transcription factors and expression of oxidative stress-inducible genes in old rats. Transcription factor and stress-response gene activation may serve as useful molecular markers for oxidant lung injury.
Am J Respir Cell Mol Biol 1995 Jul
PMID:Molecular responses to hyperoxia in vivo: relationship to increased tolerance in aged rats. 759 40

The expression patterns of the liver-enriched transcription factors CCAAT/enhancer-binding protein (C/EBP) alpha and beta and hepatocyte nuclear factor (HNF)-1 and HNF-4 were studied in liver nodules and hepatocellular carcinomas from male rats treated according to the resistant hepatocyte (RH) model. C/EBP alpha expression was lower at the transcriptional, mRNA, and protein levels in persistent nodules than in the respective surrounding livers. Expression was further decreased in the tumors. Transcriptional downregulation of C/EBP alpha gene expression was observed already in very early nodules, isolated 3 wk after partial hepatectomy in the RH model. However, no detectable changes were observed in preneoplastic nodules in the transcription or in steady-state mRNA levels of C/EBP beta, HNF-1, and HNF-4. A slight decrease in C/EBP beta protein and a more pronounced attenuation of HNF-1 and HNF-4 levels was observed in nodules, being 67%, 37%, and 46% of the levels in the corresponding surrounding livers, respectively. In conclusion, differential regulation of several transcription factors that are associated with the maintenance of the differentiated state of the hepatocytes was observed in preneoplastic and neoplastic liver lesions. This could have an impact on the regulation of a wide array of genes during liver carcinogenesis. Furthermore, the attenuation of C/EBP alpha expression, regarded as a negative growth regulator, could contribute to the proliferative advantage of nodules during liver carcinogenesis.
Mol Carcinog 1995 Feb
PMID:Expression of the liver-enriched transcription factors C/EBP alpha, C/EBP beta, HNF-1, and HNF-4 in preneoplastic nodules and hepatocellular carcinoma in rat liver. 766 15


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