scholarly journals Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes.

1989 ◽  
Vol 9 (4) ◽  
pp. 1415-1425 ◽  
Author(s):  
R H Costa ◽  
D R Grayson ◽  
J E Darnell
Keyword(s):  
Dna Binding ◽  
Transcriptional Activation ◽  
Regulatory Region ◽  
Cell Types ◽  
Specific Factor ◽  
Specific Expression ◽  
Nuclear Factors ◽  
Dna Binding Factors ◽  
Alpha 1 Antitrypsin ◽  
Different Cell Types

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.

Multiple hepatocyte-enriched nuclear factors function in the regulation of transthyretin and alpha 1-antitrypsin genes

1989 ◽  
Vol 9 (4) ◽  
pp. 1415-1425
Author(s):  
R H Costa ◽  
D R Grayson ◽  
J E Darnell
Keyword(s):  
Dna Binding ◽  
Transcriptional Activation ◽  
Regulatory Region ◽  
Cell Types ◽  
Specific Factor ◽  
Specific Expression ◽  
Nuclear Factors ◽  
Dna Binding Factors ◽  
Alpha 1 Antitrypsin ◽  
Different Cell Types

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.

scholarly journals Interactions with Single-stranded and Double-stranded DNA-binding Factors and Alternative Promoter Conformation upon Transcriptional Activation of theHtf9-a/RanBP1andHtf9-cGenes

1998 ◽  
Vol 273 (1) ◽  
pp. 495-505 ◽  
Author(s):  
Gigliola Di Matteo ◽  
Massimiliano Salerno ◽  
Giulia Guarguaglini ◽  
Barbara Di Fiore ◽  
Franco Palitti ◽  
...  
Keyword(s):  
Dna Binding ◽  
Transcriptional Activation ◽  
Alternative Promoter ◽  
Double Stranded Dna ◽  
Dna Binding Factors

scholarly journals Bromodomain protein inhibition: a novel therapeutic strategy in rheumatic diseases

RMD Open ◽  
2018 ◽  
Vol 4 (2) ◽  
pp. e000744 ◽  
Author(s):  
Kerstin Klein
Keyword(s):  
Animal Models ◽  
Rheumatic Diseases ◽  
Transcriptional Activation ◽  
Therapeutic Strategy ◽  
Cell Types ◽  
Protein Inhibition ◽  
Different Cell Types ◽  
Novel Therapeutic

The reading of acetylation marks on histones by bromodomain (BRD) proteins is a key event in transcriptional activation. Small molecule inhibitors targeting bromodomain and extra-terminal (BET) proteins compete for binding to acetylated histones. They have strong anti-inflammatory properties and exhibit encouraging effects in different cell types in vitro and in animal models resembling rheumatic diseases in vivo. Furthermore, recent studies that focus on BRD proteins beyond BET family members are discussed.

scholarly journals E4F and ATF, two transcription factors that recognize the same site, can be distinguished both physically and functionally: a role for E4F in E1A trans activation.

1990 ◽  
Vol 10 (10) ◽  
pp. 5138-5149 ◽  
Author(s):  
R J Rooney ◽  
P Raychaudhuri ◽  
J R Nevins
Keyword(s):  
Dna Binding ◽  
Binding Activity ◽  
Stable Complex ◽  
Small Subset ◽  
Adenovirus Infection ◽  
Binding Assays ◽  
Dna Binding Activity ◽  
Sequence Recognition ◽  
Nuclear Factors ◽  
Dna Binding Factors

Previous experiments have identified an element in the adenovirus E4 promoter that is critical for E1A-dependent trans activation and that can confer inducibility to a heterologous promoter. This DNA element is a recognition site for multiple nuclear factors, including ATF, which is likely a family of DNA-binding factors with similar DNA recognition properties. However, ATF activity was found not to be altered in any demonstrable way as a result of adenovirus infection. In contrast, another factor that recognizes this element, termed E4F, was found at only very low levels in uninfected cells but was increased markedly upon adenovirus infection, as measured in DNA-binding assays. Although both the ATF activity and the E4F activity recognized and bound to the same two sites in the E4 promoter, they differed in their sequence recognition of these sites. Furthermore, E4F bound only to a small subset of the ATF recognition sites; for instance, E4F did not recognize the ATF sites in the E2 or E3 promoters. Various E4F and ATF binding sites were inserted into an expression vector and tested by cotransfection assays for responsiveness to E1A. We found that a sequence capable of binding E4F could confer E1A inducibility. In contrast, a sequence that could bind ATF but not E4F did not confer E1A inducibility. We also found that E4F formed a stable complex with the E4 promoter, whereas the ATF DNA complex was unstable and rapidly dissociated. We conclude that the DNA-binding specificity of E4F as well as the alterations in DNA-binding activity of E4F closely correlates with E1A stimulation of the E4 promoter.

scholarly journals Differential Regulation of Human Interferon A Gene Expression by Interferon Regulatory Factors 3 and 7

2009 ◽  
Vol 29 (12) ◽  
pp. 3435-3450 ◽  
Author(s):  
Pierre Génin ◽  
Rongtuan Lin ◽  
John Hiscott ◽  
Ahmet Civas
Keyword(s):  
Gene Expression ◽  
Differential Expression ◽  
Transcriptional Activation ◽  
Cell Types ◽  
Inhibitory Effect ◽  
Human Interferon ◽  
Gene Promoters ◽  
Nucleotide Substitutions ◽  
D Modules ◽  
Different Cell Types

ABSTRACT Differential expression of the human interferon A (IFN-A) gene cluster is modulated following paramyxovirus infection by the relative amounts of active interferon regulatory factor 3 (IRF-3) and IRF-7. IRF-3 expression activates predominantly IFN-A1 and IFN-B, while IRF-7 expression induces multiple IFN-A genes. IFN-A1 gene expression is dependent on three promoter proximal IRF elements (B, C, and D modules, located at positions −98 to −45 relative to the mRNA start site). IRF-3 binds the C module of IFN-A1, while other IFN-A gene promoters are responsive to the binding of IRF-7 to the B and D modules. Maximal expression of IFN-A1 is observed with complete occupancy of the three modules in the presence of IRF-7. Nucleotide substitutions in the C modules of other IFN-A genes disrupt IRF-3-mediated transcription, whereas a G/A substitution in the D modules enhances IRF7-mediated expression. IRF-3 exerts dual effects on IFN-A gene expression, as follows: a synergistic effect with IRF-7 on IFN-A1 expression and an inhibitory effect on other IFN-A gene promoters. Chromatin immunoprecipitation experiments reveal that transient binding of both IRF-3 and IRF-7, accompanied by CBP/p300 recruitment to the endogenous IFN-A gene promoters, is associated with transcriptional activation, whereas a biphasic recruitment of IRF-3 and CBP/p300 represses IFN-A gene expression. This regulatory mechanism contributes to differential expression of IFN-A genes and may be critical for alpha interferon production in different cell types by RIG-I-dependent signals, leading to innate antiviral immune responses.

scholarly journals A Dominant-Negative Inhibitor of CREB Reveals that It Is a General Mediator of Stimulus-Dependent Transcription of c-fos

1998 ◽  
Vol 18 (2) ◽  
pp. 967-977 ◽  
Author(s):  
Sohyun Ahn ◽  
Michelle Olive ◽  
Seema Aggarwal ◽  
Dmitry Krylov ◽  
David D. Ginty ◽  
...  
Keyword(s):  
Dna Binding ◽  
Pc12 Cells ◽  
Transcriptional Activation ◽  
Cortical Neurons ◽  
Leucine Zipper ◽  
Uv Light ◽  
Regulatory Region ◽  
Dominant Negative ◽  
Intracellular Camp ◽  
Basic Region

ABSTRACT Several studies have characterized the upstream regulatory region of c-fos, and identified cis-acting elements termed the cyclic AMP (cAMP) response elements (CREs) that are critical for c-fos transcription in response to a variety of extracellular stimuli. Although several transcription factors can bind to CREs in vitro, the identity of the transcription factor(s) that activates the c-fos promoter via the CRE in vivo remains unclear. To help identify the trans-acting factors that regulate stimulus-dependent transcription of c-fos via the CREs, dominant-negative (D-N) inhibitor proteins that function by preventing DNA binding of B-ZIP proteins in a dimerization domain-dependent fashion were developed. A D-N inhibitor of CREB, termed A-CREB, was constructed by fusing a designed acidic amphipathic extension onto the N terminus of the CREB leucine zipper domain. The acidic extension of A-CREB interacts with the basic region of CREB forming a coiled-coil extension of the leucine zipper and thus prevents the basic region of wild-type CREB from binding to DNA. Other D-N inhibitors generated in a similar manner with the dimerization domains of Fos, Jun, C/EBP, ATF-2, or VBP did not block CREB DNA binding activity, nor did they inhibit transcriptional activation of a minimal promoter containing a single CRE in PC12 cells. A-CREB inhibited activation of CRE-mediated transcription evoked by three distinct stimuli: forskolin, which increases intracellular cAMP; membrane depolarization, which promotes Ca2+ influx; and nerve growth factor (NGF). A-CREB completely inhibited cAMP-mediated, but only partially inhibited Ca2+- and NGF-mediated, transcription of a reporter gene containing 750 bp of the native c-fos promoter. Moreover, glutamate induction of c-fos expression in primary cortical neurons was dependent on CREB. In contrast, induction of c-fos transcription by UV light was not inhibited by A-CREB. Lastly, A-CREB attenuated NGF induction of morphological differentiation in PC12 cells. These results suggest that CREB or its closely related family members are general mediators of stimulus-dependent transcription of c-fos and are required for at least some of the long-term actions of NGF.

scholarly journals Complex regulation and functional versatility of mammalian alpha- and beta-tubulin isotypes during the differentiation of testis and muscle cells.

1988 ◽  
Vol 106 (6) ◽  
pp. 2023-2033 ◽  
Author(s):  
S A Lewis ◽  
N J Cowan
Keyword(s):  
Cell Types ◽  
Beta Tubulin ◽  
Specific Expression ◽  
Alpha Tubulin ◽  
Tubulin Isotypes ◽  
Tubulin Isotype ◽  
A Cell ◽  
Complex Regulation ◽  
Carboxy Terminal ◽  
Different Cell Types

In the accompanying paper (Gu, W., S. A. Lewis, and N. J. Cowan. 1988. J. Cell Biol. 106: 2011-2022), we report the generation of three antisera, each of which uniquely recognizes a different mammalian alpha-tubulin isotype, plus a fourth antibody that distinguishes between microtubules containing the tyrosinated and nontyrosinated form of the only known mammalian alpha-tubulin gene product that lacks an encoded carboxy-terminal tyrosine residue. These sera, together with five sera we raised that distinguish among the known mammalian beta-tubulin isotypes, have been used to study patterns of tubulin isotype-specific expression in muscle and testis, two tissues in which characteristic developmental changes are accompanied by dramatic rearrangements in microtubule structures. As in the case of cells in culture, there is no evidence to suggest that there is subcellular sorting of different tubulin isotypes among different kinds of microtubule, even in a cell type (the developing spermatid) that simultaneously contains such functionally distinct structures as the manchette and the flagellum. On the other hand, the patterns of expression of the various tubulin isotypes show marked and distinctive differences in different cell types and, in at least one case, evidence is presented for regulation at the translational or posttranslational level. The significance of these observations is discussed in terms of the existence of the mammalian alpha- and beta-tubulin multigene families.

Transcriptional activation by the human Hsp70-associating protein Hap50

2001 ◽  
Vol 114 (10) ◽  
pp. 1839-1845
Author(s):  
Y. Niyaz ◽  
M. Zeiner ◽  
U. Gehring
Keyword(s):  
Transcriptional Activation ◽  
Fluorescent Protein ◽  
Biological Effects ◽  
Cell Types ◽  
Mrna Stabilization ◽  
Activation Of Transcription ◽  
Enhanced Expression ◽  
Endogenous Genes ◽  
Green Fluorescent ◽  
Different Cell Types

We investigated human Hap50, the large isoform of the previously characterized Hsp70/Hsc70-associating protein Hap46, also called BAG-1, for effects on transcriptional activities. Overproduction by transient transfection led to enhanced expression of reporter gene constructs in various cell types using different promoters, suggesting independence of promoter type. Similarly, overexpression of Hap50 resulted in increased levels of poly(A)(+)mRNAs in HeLa, COS-7, 3T3 and HTC cells. Concomitantly, the expression of some selected endogenous genes, such as those coding for c-Jun and the glucocorticoid receptor, was enhanced significantly relative to actin. Nuclear runoff transcription assays using HeLa cells showed that the effect is caused by increased transcription rates rather than mRNA stabilization. Activation of transcription by Hap50 occurred at 37 degrees C and did not require prior thermal stress, as is the case for Hap46. In accordance with these biological effects, Hap50 is localized exclusively in the nuclear compartment of different cell types, whereas Hap46 is mostly cytoplasmic in unstressed cells, as revealed by use of fusion constructs with green fluorescent protein. High cellular levels of Hap50 were found to make cells less susceptible to adverse environmental effects such as heat stress. Our data suggest that Hap50 is a nuclear protein that acts in cells to increase the transcription of various genes.

scholarly journals A Cluster of Four Surface Antigen Genes Specifically Expressed in Bradyzoites, SAG2CDXY, Plays an Important Role in Toxoplasma gondii Persistence

2008 ◽  
Vol 76 (6) ◽  
pp. 2402-2410 ◽  
Author(s):  
Jeroen P. J. Saeij ◽  
Gustavo Arrizabalaga ◽  
John C. Boothroyd
Keyword(s):  
Toxoplasma Gondii ◽  
Surface Antigen ◽  
Chronic Infection ◽  
Cell Types ◽  
Firefly Luciferase ◽  
Specific Expression ◽  
Genes Encoding ◽  
Tandem Genes ◽  
Different Cell Types ◽  
The Brain

ABSTRACT Toxoplasma gondii is one of the most successful protozoan parasites of warm-blooded animals. Stage-specific expression of its surface molecules is thought to be key to its ability to establish chronic infection in immunocompetent animals. The rapidly dividing tachyzoite stage displays a different subset of family of surface antigen 1 (SAG1)-related sequences (SRSs) from that displayed by the encysted bradyzoite stage. It is possible that this switch is necessary to protect the bradyzoites against an immune response raised against the tachyzoite stage. Alternatively, it might be that bradyzoite SRSs evolved to facilitate invasion of different cell types, such as those found in the brain, where cysts develop, or the small intestine, where bradyzoites must enter after oral infection. Here we studied the function of a cluster of four tandem genes, encoding bradyzoite SRSs called SAG2C, -D, -X, and -Y. Using bioluminescence imaging of mice infected with parasites expressing firefly luciferase (FLUC) driven by the SAG2D promoter, we show stage conversion for the first time in living animals. A truncated version of the SAG2D promoter (SAG2Dmin) gave efficient expression of FLUC in both tachyzoites and bradyzoites, indicating that the bradyzoite specificity of the complete SAG2D promoter is likely due to an element(s) that normally suppresses expression in tachyzoites. Comparing mice infected with the wild type or a mutant where the SAG2CDXY cluster of genes has been deleted (ΔSAG2CDXY), we demonstrate that whereas ΔSAG2CDXY parasites are less capable of maintaining a chronic infection in the brain, they do not show a defect in oral infectivity.

scholarly journals Molecular characterization of Xenopus laevis DP proteins.

1994 ◽  
Vol 5 (10) ◽  
pp. 1081-1092 ◽  
Author(s):  
R Girling ◽  
L R Bandara ◽  
E Ormondroyd ◽  
E W Lam ◽  
S Kotecha ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Binding ◽  
Xenopus Laevis ◽  
Transcriptional Activation ◽  
Mammalian Cells ◽  
Cell Cycle Progression ◽  
Close Relative ◽  
Specific Expression ◽  
Related Proteins ◽  
Dna Binding Complexes

It is widely believed that in mammalian cells the cellular transcription factor (DRTF1/E2F integrates cell-cycle events with the transcription apparatus by interacting with important regulators of the cell cycle, such as the retinoblastoma gene product (pRb) and related proteins, cyclins, and cyclin-dependent kinases. Here, we have defined DRTF1/E2F in Xenopus laevis that, like its mammalian counterpart, specifically binds to the E2F site, is regulated during development, and interacts with pRb and related proteins. We have isolated cDNAs that encode the functional homologue of mammalian DP-1, X1 DP-1, together with a close relative, X1 DP-2. X1 DP-1, which is highly conserved with murine DP-1, is a major DNA binding component of X1 DRTF1/E2F. Both DP-1 and DP-2 synergistically interact with members of the E2F family of proteins, E2F-1, E2F-2, and E2F-3, to generate DNA binding complexes that specifically recognize the E2F site and functionally interact with E2F-1 in E2F site-dependent transcriptional activation of cellular genes. DP-1 and DP-2 encode maternally stored transcripts that are expressed during early development. In the adult however, the expression of DP-1 and DP-2 is tissue restricted. This study therefore defines a new family of transcription factors, the DP proteins, members of which can interact combinatorially with E2F proteins to generate an array of DNA binding complexes that integrate cell-cycle progression with the transcription apparatus through the E2F binding site. The tissue-specific expression of DP family members suggests that the combination of DP/E2F heterodimers that constitute DRTF1/E2F is influenced by the phenotype of the cell.

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