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PubMed1992

Human smooth muscle myosin light chain-2 gene expression is repressed in ras transformed fibroblast cells.

We have previously characterized human smooth muscle myosin light chain (MLC)-2 isoform by complementary DNA cloning and have shown that this isoform is expressed in a number of nonmuscle cells such as fibroblast cells. In this report, we show that when human osteosarcoma derived clonal cells (TE 85 clone F-5) (HOS), which are immortalized and nontumorigenic, undergo transformation following infection by Kirsten murine sarcoma virus (K-HOS) or by a chemical carcinogen [N-methyl-N-nitro-N-nitrosoguanidine (MNNG-HOS)], the smooth muscle MLC-2 mRNA is repressed. Revertants of transformed K-HOS cells (K-HOS312H) show normal levels of smooth muscle MLC-2 mRNA. Transformation of HOS cells by Ha-ras oncogene sequences, either by retroviral infection or by transfection followed by selection for tumorigenic cells in nude mice, results in complete repression of smooth muscle MLC-2 mRNA level. Treatment of HOS cells with tumor promoting phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, results in repression of smooth muscle MLC-2 mRNA. Smooth muscle MLC-2 mRNA level is repressed in many, but not all, transformed cell lines, suggesting that it is not an indirect consequence of transformation but is specific to the agent that brings about transformation. HOS cells synthesize three MLC-2 protein species resolved by the two-dimensional gel electrophoretic system. The identity of the smooth muscle MLC-2 isoform was established by coelectrophoresis of the in vitro synthesized MLC-2 protein corresponding to the cloned complementary DNA in the two-dimensional gel system along with total [35S]methionine labeled HOS cell proteins. Quantitative analysis of MLC-2 isoforms in different HOS cells indicates that the synthesis of smooth muscle MLC-2 isoform is specifically repressed to an undetectable level in ras transformed and MNNG transformed cells and also following treatment with 12-O-tetradecanoylphorbol-13-acetate.

Cell Line, Transformed↗
PubMed1991

Repression of the chicken c-rel promoter by vRel in chicken embryo fibroblasts is not mediated through a consensus NF-kappa B binding site.

To understand the regulation of expression of the chicken c-rel gene, we cloned genomic sequences upstream of the start site of transcription of c-rel. Sequence analysis shows that the c-rel promoter is a GC-rich promoter that lacks a TATA box. In addition, there are putative binding sites for several transcription factors, including an NF-kappa B consensus binding site. Primer extension showed that there is one major start site (site 1) for transcription in chicken embryo fibroblasts and two major start sites in a v-rel-transformed chicken spleen cell line. In transient assays using c-rel promoter sequences and the CAT reporter gene, we found that vRel repressed expression from the c-rel promoter. Other viral oncoproteins and a non-transforming v-rel deletion mutant did not repress the c-rel promoter. Repression occurred through sequences located within 125 bp of the start of transcription. However, mutation of the consensus NF-kappa B binding site did not affect the level of transcription from the c-rel promoter, nor did it interfere with repression by vRel, even though vRel could bind to the wild-type, but not the mutant, version of this sequence in vitro. These results suggest that the vRel protein can repress transcription through an indirect mechanism.

Animals↗
PubMed1990

Adenovirus E1A represses protease gene expression and inhibits metastasis of human tumor cells.

Stable transfection of human tumor cell lines with the adenovirus-5 E1A gene repressed the expression of the secreted proteases, type IV collagenase, interstitial collagenase and urokinase. In addition, E1A blocked the 12-O-tetradecanoyl phorbol acetate (TPA) induction of interstitial collagenase transcription in HT1080 fibrosarcoma cells. Plasmids bearing the interstitial collagenase or type IV collagenase 5' flanking regions linked to a chloramphenicol acetyl transferase coding sequence were constructed and analysed for expression by transient cotransfections into HT1080 cells. Cotransfection with a plasmid bearing a functional E1A gene repressed transcription of the type IV collagenase promoter and blocked the TPA induction of the interstitial collagenase promoter. Furthermore, E1A repressed transcription from a TK promoter driven by AP-1 complex binding sites (TRE), suggesting that E1A interferes with the AP-1 trans-activation pathway. This effect was not, however, due to the repression of c-jun gene transcription by E1A. In fact, the expression of E1A rendered the c-jun gene hypersensitive to TPA induction. Concomitant with reduction in expression levels of secreted proteases, stable E1A transfectants showed reduced metastatic activity in vivo and reduced ability to traverse a reconstituted basement membrane in vitro. Monospecific anti-type IV collagenase antibodies inhibited invasive activity of parental tumor cell lines in the in vitro assay, suggesting a possible causal relationship between the repression of secreted proteases and loss of metastatic properties of the transformants.

Adenovirus Early Proteins↗
PubMed1989

Identity of soluble thiamine-binding protein with thiamine repressible acid phosphatase in Saccharomyces cerevisiae.

Two secretory glycoproteins of S. cerevisiae, a soluble thiamine-binding protein and a thiamine-repressible acid phosphatase, were shown to be repressed to a similar extent by excess thiamine in the growth medium. Thiamine-repressible acid phosphatase was co-purified throughout the purification of the soluble thiamine-binding protein. Purified and deglycosylated soluble thiamine-binding proteins exhibited both thiamine-binding and acid phosphatase activities on non-denaturing polyacrylamide gel electrophoresis. Heat treatment of the purified soluble thiamine-binding protein caused a decrease in both activities with a similar inactivation profile. Two thiamine-repressible acid phosphatase-defective mutants isolated were found to be also defective in soluble thiamine-binding activity. The uptake of [14C]thiamine phosphate esters, such as thiamine monophosphate and thiamine pyrophsphate, was remarkably impaired in the mutant cells, whereas the uptake of [14C]thiamine by the mutant was almost the same with that by the parent strain. From these results, it was concluded that the soluble thiamine-binding protein is identical to the thiamine-repressible acid phosphatase in S. cerevisiae, which is involved in the hydrolysis of exogenous thiamine phosphate esters in the periplasmic space prior to the uptake of their thiamine moiety by yeast cells.

Acid Phosphatase↗
PubMed1989

Requirements for the translational repression of ferritin transcripts in wheat germ extracts by a 90-kDa protein from rabbit liver.

A specific repressor of ferritin mRNA translation originally detected in rabbit reticulocyte lysates has now been purified to homogeneity from rabbit liver, as described in a companion paper (Walden, W. E., Patino, M. M., and Gaffield, L. (1989) J. Biol. Chem. 264, 13765-13769). This repressor is a 90-kDa protein that binds to a sequence in the 5'-untranslated region of ferritin mRNA. In this communication we describe the molecular features of a ferritin light chain transcript that are required for the repression of its translation by this protein. Addition of small amounts of the 90-kDa ferritin repressor protein (FRP) completely inhibited translation of ferritin transcripts in a wheat germ system. This repression did not require mRNA sequences contained in the 3'-untranslated region or in the majority of the ferritin coding region. In contrast, the first 130 nucleotides of the 5'-untranslated region, which contains the 28-nucleotide "iron responsive element" (IRE), was required for the repressive effect. Moreover, repression of full length transcripts was relieved by addition of a molar excess of a 92-nucleotide transcript of the 5'-untranslated region which also contained the IRE. These results suggest that no sequence information other than a portion of the 5'-untranslated region containing the IRE sequence is required for action of the 90-kDa FRP. In addition, a quantitative comparison of the repression of transcript with that of poly(A+) RNAs indicates that no post-transcriptional modifications of the latter (other than cap addition) are involved in the action of the 90-kDa FRP.

Animals↗
PubMed1994

Selective repression of growth-regulating cdk2, cyclin E and E2F1 genes in human cell senescence.

Normal human diploid TIG-1 fibroblasts underwent replicative senescence around 64-68 population doubling levels (PDL) by the irreversible serum-unresponsive G1-growth arrest. Repression of growth-promoting genes was searched in this study. The RT-PCR and Western blot analyses have shown that in senescent TIG-1 cells at PDL64-67, cdk2 and cyclin E were selectively repressed at the mRNA and protein levels even after serum stimulation, and cdc2 and cyclin A were less repressed than cdk2 and cyclin E. Such a specific lack of cdk2 and cyclin E proteins correlated with unphosphorylation of the retinoblastoma gene product (pRB) in senescent cells. Transcription factor E2F1 was also completely repressed at the mRNA and protein levels in senescent TIG-1 cells. Middle-passage cells exhibited active expressions of all the above genes and pRB phosphorylation. Therefore, the present results have indicated the selective repressions of cdk2, cyclin E and E2F1 in senescent cells.

Base Sequence↗
PubMed1994

Human hepatitis virus X gene encodes a regulatory domain that represses transactivation of X protein.

The human hepatitis B virus (HBV) X gene seems to be essential for establishment of viral infection, and the X gene product, HBx, transactivates virus and host genes through a wide variety of cis-elements, whereas regulation of HBx has not been fully understood. We found that transactivation-negative HBx mutants truncated at the C-terminal portion specifically repressed the HBx transactivation in trans. The ability to trans-repress the HBx transactivation is confined to the N-terminal third of HBx. Transactivation-positive constructs of HBx were divided into two groups by their sensitivity to trans-repression due to the presence of the N-terminal third. Thus the regulatory domain, the N-terminal third, is separated from the transacting domain and responsible for the negative regulations, the trans-repression and sensitivity to X trans-repression. A possible direct association between the HBx regulatory domains was tested by far-Western blotting using purified fused forms of HBx proteins. The regulatory domain was found to associate preferentially with the full HBx or the regulatory domain, but not with the transacting domain. Taken together, it is possible that HBx has a self-regulatory mechanism that avoids excessive HBx transactivation and is important for regulation of X gene expression.

Binding Sites↗
PubMed1993

Preferential repression of the H subunit of ferritin by adenovirus E1A in NIH-3T3 mouse fibroblasts.

Ferritin is the major intracellular iron-storage protein in eucaryotic cells and plays a prominent role in maintaining intracellular iron homeostasis. We observed that transfection of NIH-3T3 mouse fibroblasts with the adenovirus E1A oncogene specifically repressed the mRNA for one of the subunits of ferritin, ferritin H. This occurred in the absence of any effect of E1A on the mRNA for the L subunit of ferritin. The repression of ferritin H was not a general feature of oncogene expression since transfection of NIH-3T3 cells with H-ras did not affect ferritin composition. Deletion of the conserved regions of E1A responsible for immortalization and transcriptional repression impaired the ability of E1A to repress ferritin H. Immunoprecipitation of ferritin in E1A transfectants demonstrated that the decrease in the ferritin H/L ratio observed at the mRNA level was also exhibited at the protein level. The E1A-dependent inhibition of ferritin H was also observed in a chimeric gene containing the ferritin H promoter ligated to the chloramphenicol acetyltransferase reporter gene, but was not observed in control genes in which chloramphenicol acetyltransferase activity was dependent on promoters derived from SV40 or the interleukin-3 gene. This suggests that E1A may repress ferritin H at the transcriptional level. These results demonstrate that the adenovirus E1A oncogene specifically modulates ferritin H expression. They also suggest that alterations in cellular iron metabolism may be among the diverse array of cellular responses induced by E1A.

3T3 Cells↗
PubMed1996

Activation and repression of transcription at two different phage phi29 promoters are mediated by interaction of the same residues of regulatory protein p4 with RNA polymerase.

Phage phi29 regulatory protein p4 activates transcription from the late A3 promoter and represses the main early promoters, named A2b and A2c. Activation involves stabilization of RNA polymerase (RNAP) at the A3 promoter as a closed complex and is mediated by interaction between RNAP and a small domain of protein p4 in which residue Arg120 plays an essential role. We show that protein p4 represses the A2c promoter by binding to DNA immediately upstream from RNAP in a way that does not hinder RNAP binding; rather, the two proteins bind cooperatively to DNA. In the presence of protein p4, RNAP can form an initiated complex at the A2c promoter that generates short abortive transcripts, but cannot leave the promoter. Mutation of protein p4 residue Arg120, which relieves the contact between the two proteins, leads to a loss of repression. Therefore, the contact between protein p4 and RNAP through the protein p4 domain containing Arg120 can activate or repress transcription, depending on the promoter. The relative position of protein p4 and RNAP, which is different at each promoter, together with the distinct characteristics of the two promoters, may determine whether protein p4 activates or represses transcription.

Amino Acid Sequence↗
PubMed1996

All four core histone N-termini contain sequences required for the repression of basal transcription in yeast.

Nucleosomes prevent the recognition of TATA promoter elements by the basal transcriptional machinery in the absence of induction. However, while Saccharomyces cerevisiae histones H3 and H4 contain N-terminal regions involved in the activation and repression of GAL1 and in the expression of heterochromatin-like regions, the sequences involved in repressing basal transcription have not yet been identified. Here, we describe the mapping of new N-terminal domains, in all four core histones (H2A, H2B, H3 and H4), required for the repression of basal, uninduced transcription. Basal transcription was monitored by the use of a GAL1 promoter-URA3 reporter construct whose uninduced activity can be detected through cellular sensitivity to the drug, 5-fluoroorotic acid. We have found for each histone that the N-terminal sequences repressing basal activity are in a short region adjacent to the structured alpha-helical core. Analysis of minichromosome DNA topology demonstrates that the basal domains are required for the proper folding of DNA around the chromosomal particle. Deletion of the basal domain at each histone significantly decreases plasmid superhelical density, which probably reflects a release of DNA from the constraints of the nucleosome into the linker region. This provides a means by which basal factors may recognize otherwise repressed regulatory elements.

Acetylation↗
PubMed1996

Direct and indirect mechanisms of repression participate in suppression of T-cell-specific gene expression in T x L-cell hybrids.

Expression of tissue-specific genes can be altered upon fusion of mammalian cells of different types. To resolve the genetic basis of this phenomenon and to identify components of the regulatory circuits that are involved, we have established a series of somatic cell hybrids between mouse T cells and L cells. These hybrids have an unusual and interesting phenotype. Unlike many hybrid cells studied, in which the expression of an entire set of tissue-specific genes was coordinately extinguished, in our T x L-cell hybrids only two out of seven T-cell-restricted genes were completely extinguished, whereas the other genes were repressed to various degrees. These hybrids extinguish the production of TCR beta and Thy-1 mRNA, repress the expression of TCR alpha, GATA-3, TCF-1, and LEF-1 genes to different extents, exhibit small changes in the level of CD3-epsilon mRNA, and continue to express the fibroblast-specific fibronectin gene, and the ets-1 gene. In this study we have evaluated for the first time the molecular mechanisms that underlie the repression of TCR alpha and TCR beta chain genes in T x L-cell hybrids. We have shown that multiple repression mechanisms, both direct and indirect, contribute to TCR alpha and TCR beta suppression. Repression of the expression of these genes correlated not only with the downregulation of GATA-3, TCF-1, and LEF-1 transcription factor expression, and with a change in the chromatin structure, but more importantly, with the activation of the silencer activity. Our study provides evidence for the existence of at least two negatively regulating elements, located at the TCR alpha enhancer-containing fragment and at the silencer region, which are active in our hybrid cells. We have shown that there was no correlation between the levels of GATA-3, TCF-1, and LEF-1 expression versus the level of TCR alpha mRNA in the independent hybrids. In contrast, both the silencer activity and the ability of the TCR alpha enhancer to downregulate thymidine kinase (TK) promoter activity were found to be in an inverse correlation with the ability of the different hybrid cells to express TCR alpha mRNA.

Animals↗
PubMed1997

Improvement of the production of foreign proteins using a heterologous secretion vector system in Bacillus subtilis: effects of resistance to glucose-mediated catabolite repression.

To improve protein production, a heterologous secretion vector system was constructed with the aid of the amyR2 region. The operator sequence (amyO) of the amyR2 region on the secretion vector was changed through site-directed mutagenesis to eliminate carbon-source-mediated catabolite repression. Three substitutional (AG, G5, G10), one deletional (delta HH), and one insertional (AGHF) mutant promoters were obtained. The expression level and the degree of catabolite repression of amyR2 and the mutant promoters were examined with a single copy system using an integrational promoter probe vector, pDH32. Under glucose-free culture conditions, expression levels from all mutant promoters except HH were 1.4 to 1.5 fold higher than that from amyR2. While the expression of the amyR2 promoter was repressed by 90% in the presence of 2% glucose, expression levels of the mutant promoters were repressed by only 1% to 50%. To evaluate the advantage of the mutant promoters in production of foreign proteins by the heterologous secretion system, beta-lactamase and human pancreatic secretory trypsin inhibitor (hPSTI) were expressed by the mutant promoters. When B. subtilis LKS87 was used as a host strain, the production of the target proteins using the respective mutant promoter was increased by about 1.5 fold under glucose-free culture conditions. Under the high glucose culture conditions, secretion of target proteins produced from the mutant promoters increased 1.5 to 2 fold, whereas those by the amyR2 promoter were reduced to between 50% and 60%. The additive effect of degUh mutation on protein production was not observed under high glucose culture conditions. In addition, such culture conditions inhibited proteolytic degradation of secreted target proteins after the stationary growth phase even in B. subtilis LKS88 (degUh mutant). Thus, our results indicated that the mutant promoters, which are resistant to glucose-mediated catabolite repression, are very useful for over-production of foreign proteins under the high glucose culture conditions using the heterologous expression-secretion system in B. subtilis.

Bacillus subtilis↗
PubMed1998

CDF-1 mediated repression of cell cycle genes targets a specific subset of transactivators.

The cdc25C, cyclin A and cdc2 genes are regulated during the cell cycle through two contiguous repressor binding sites, the CDE and CHR, located in the region of transcription initiation and interacting with a factor termed CDF-1. The target of this repression seems to be transcriptional activation of these promoters by transcription factors bound upstream. The majority of these factors falls into the class of glutamine-rich activators, suggesting that CDF-1-mediated repression might be activation domain specific. In the present study we have used chimeric promoter constructs to demonstrate that the cdc25C UAS, but not the core promoter, is crucial for repression. In addition, we show that only specific transcription factors and activation domains are responsive to CDE-CHR-mediated cell cycle regulation. These observations clearly indicate that CDF-1 interferes with activation of transcription by a specific subset of transactivators. The repressible activation domains belong to the same class of glutamine-rich activators, pointing to specific interactions of CDF-1 with components of the transcription machinery. In agreement with this conclusion we find that a simple inversion of the CDF-CHR module completely abrogates cell cycle-regulated repression.

3T3 Cells↗
PubMed1998

Accumulation of p300 mediates transcriptional repression of simian virus 40 enhancer in undifferentiated F9 embryonal carcinoma cells.

The SV40 enhancer is repressed in embryonal carcinoma (EC) cells, and it is also repressed by the adenovirus E1A oncoprotein. Repression by E1A is mediated by the binding of E1A to the p300 transcriptional coactivator. Thus, we examined the role of p300 in the repression of the SV40 enhancer activity in EC cells. We demonstrated that high levels of p300 protein are accumulated in undifferentiated EC cells and that the levels decline dramatically upon differentiation because of the changes of protein stability. Furthermore, we showed that overexpression of p300 does not stimulate the SV40 enhancer activity in undifferentiated F9 cells. However, the activity of a p300 mutant deficient for E1A binding can be restored by the presence of excess E1A. In addition, low-level expression of E1A causes derepression of the enhancer activity in F9 cells. These results indicate that the accumulation of p300 protein participates in repression of the SV40 enhancer activity in undifferentiated F9 cells.

Activating Transcription Factor 1↗
PubMed2000

Construct validity of repression: a dimensional analysis.

This study explored the construct validity of repression through an examination of the interrelations among indicators identified in previous research as being associated with the construct. Three behavioral tasks, i.e., dichotic listening task, recall of past events task, and Stroop task, modified in accordance with previous research to tap into repressive tendencies, and one questionnaire (Byrne Repression-Sensitization Scale) were administered to a sample of 62 university undergraduates. A series of correlational analyses provided weak to moderate support for the construct validity of repression.

Adult↗
PubMed1994

A Polycomb response element in the Ubx gene that determines an epigenetically inherited state of repression.

Segmentation genes provide the signals for the activation and regulation of homeotic genes in Drosophila but cannot maintain the resulting pattern of expression because their activity ceases halfway through embryogenesis. Maintenance of the pattern is due to the Polycomb group of genes (Pc-G) and the trithorax group of genes (trx-G), responsible for the persistence of the active or repressed state of homeotic genes. We have identified a regulatory element in the Ubx gene that responds to Pc-G and trx-G genes. Transposons carrying this element create new binding sites for Pc-G products in the polytene chromosomes. This Pc-G maintenance element (PRE), establishes a repressive complex that keeps enhancers repressed in cells in which they were originally repressed and maintains this state through many cell divisions. The trx-G products stimulate the expression of enhancers in cells in which they were originally active. This mechanism is responsible for the correct regulation of imaginal disc enhancers, which lack themselves antero-posterior positional information. The PRE also causes severe variegation of the mini-white gene present in the transposon, a phenomenon very similar to heterochromatic position-effect variegation. The significance of this mechanism for homeotic gene regulation is discussed.

Animals↗
PubMed1994

Quality and position of the three lac operators of E. coli define efficiency of repression.

Repression of the lac promoter may be achieved in two different ways: either by interference with the action of RNA polymerase or by interference with CAP activation. We investigated cooperative repression of the Escherichia coli lac operon by systematic conversion of its three natural operators (O1, O2 and O3) on the chromosome. We find that cooperative repression by tetrameric Lac repressor increases with both quality and proximity of the interacting operators. A short distance of 92 bp allows effective repression by two very weak operators (O3, O3). The cooperativity of lac operators is discussed in terms of a local increase of repressor concentration. This increase in concentration depends on flexible DNA which allows loop formation.

Base Sequence↗
PubMed2005

To repress: a note on an ambiguity of meaning.

An analysand used the word repress in a dream in an unusual way. In the dream, a record had been re-pressed: it was not the original disc but a copy. This manifest meaning of the word led associatively to more latent meanings. A kind of dialectical process ensued whereby, whenever the concept of repression came up, several meanings had to be considered to set the record straight. The classical way of thinking about repression had been augmented a little by this novel meaning that the analysand had stumbled on in his dream. Psychoanalytic process was enriched by this ongoing scrutiny of repression in theory and practice.

Humans↗