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At least 1,315 records · Page 73Linked to original sources
PubMed2001

The tRNA function of SsrA contributes to controlling repression of bacteriophage Mu prophage.

The small regulatory RNA SsrA has both tRNA and mRNA activities. It charges alanine and interacts with stalled ribosomes, allowing for translation to resume on the SsrA mRNA moiety. Hence, unfinished peptides carry a short amino acid tag, which serves as a signal for degradation by energy-dependent proteases. In SsrA-defective Escherichia coli strains, thermoinducible mutants of the transposable bacteriophage Mu (Mucts) are no longer induced at high temperature. Here we show that truncated forms of the key regulator of Mu lysogeny, the repressor Repc, accumulate in the absence of SsrA. These forms resemble C-terminally truncated dominant Mu repressor mutants previously isolated from Mucts, which are no longer thermoinducible and bind operator DNA with a high affinity even at high temperature. Using various ssrA alleles, we demonstrate the importance of SsrA charging on the ribosome for controlling Mu prophage repression. Our results thus substantiate the previous observation that trans-translation is not the only function of the SsrA. The alternative function of SsrA appears to influence the stability of Mu lysogens by controlling the translation of the C-terminal domain of the repressor protein, which modulates the affinity of the protein for DNA and its susceptibility to proteolytic degradation.

Alanine↗
PubMed1989

Sequences that surround the stop codons of upstream open reading frames in GCN4 mRNA determine their distinct functions in translational control.

Translational control of the GCN4 gene of Saccharomyces cerevisiae requires at least two of the four short upstream open reading frames (URFs) in the leader of GCN4 mRNA. URF4 is a strong negative element that is sufficient for repression of GCN4 expression in normal growth conditions. URF1 is approximately 30-fold less effective as a translational barrier when it is the single URF present in the mRNA leader and is required upstream from URF4 for efficient derepression of GCN4 expression under amino acid starvation conditions. We show that the last codon plus 10 bp immediately after the stop codon of URF4 are sufficient to convert URF1 into a strong translational barrier when it is present as a solitary URF. This result suggests that the characteristics of translation termination at URF4 are responsible largely for its strong inhibitory effect on translation initiation at the GCN4 AUG codon. Introduction of the same URF4 sequences at URF1 also reduces GCN4 expression under derepressing conditions when URF1 is upstream from URF4. This fact suggests that URF1 translation normally is compatible with efficient scanning and initiation downstream and that this property is required for its ability to overcome the translational barrier at URF4. These findings are consistent with the idea that ribosomes must first translate URF1 and then resume scanning in order to traverse URF4 sequences under starvation conditions. Our results indicate that nucleotides located 3' to the stop codon can be as important as those located 5' to the start site in determining the inhibitory effect of an URF on translation initiation downstream.

Base Sequence↗
PubMed2006

Raf plus TGFbeta-dependent EMT is initiated by endocytosis and lysosomal degradation of E-cadherin.

Oncogenic Ras interferes with adhesive functions of epithelial cells, but requires tumor growth factor beta (TGFbeta) signaling to cause epithelial-mesenchymal transition (EMT) and tumor progression in model systems. To investigate the mechanisms by which Ras and TGFbeta pathways cooperate in EMT induction, we introduced a tamoxifen-inducible version of Raf-1 (RafER) into fully polarized, mammary epithelial cells (EpH4). EMT characterized by loss of E-cadherin expression and upregulation of invasiveness-promoting genes was induced by TGFbeta plus 4-hydroxytamoxifen (4HT) activation of RafER. Downregulation of E-cadherin by RafER plus TGFbeta was detectable in total cell lysates after 48 h and much earlier in detergent-insoluble fractions of E-cadherin. Both pathways cooperated to strongly enhance endocytosis of E-cadherin, mainly via the clathrin-dependent route. Pulse-chase experiments showed decreased E-cadherin protein stability in cells stimulated with TGFbeta and 4HT and increased E-cadherin half-life in the presence of monensin. Monensin and chloroquine prevented E-cadherin degradation to different extent, but only monensin effectively blocked the loss of E-cadherin from the junctional complexes. Both lysosome inhibitors caused accumulation of E-cadherin vesicles, some of which were positive for Cathepsin D and lysosome-associated membrane protein 1 (LAMP-1). In addition, TGFbeta and mitogen-activated protein kinase hyperactivation synergistically induced E-cadherin ubiquitination, suggesting that the cooperation of Raf and TGFbeta favors lysosomal degradation of E-cadherin instead of its recycling. Our data indicate that early stages of EMT involve cooperative, post-translational downregulation of E-cadherin, whereas loss of E-cadherin via transcriptional repression is a late event in EMT.

Animals↗
PubMed2000

Identification of an effector specificity subregion within the aromatic-responsive regulators DmpR and XylR by DNA shuffling.

The Pseudomonas derived sigma(54)-dependent regulators DmpR and XylR control the expression of genes involved in catabolism of aromatic compounds. Binding to distinct, nonoverlapping groups of aromatic effectors controls the activities of these transcriptional activators. Previous work has derived a common mechanistic model for these two regulators in which effector binding by the N-terminal 210 residues (the A-domain) of the protein relieves repression of an intrinsic ATPase activity essential for its transcription-promoting property and allows productive interaction with the transcriptional apparatus. Here we dissect the A-domains of DmpR and XylR by DNA shuffling to identify the region(s) that mediates the differences in the effector specificity profiles. Analysis of in vivo transcription in response to multiple aromatic effectors and the in vitro phenol-binding abilities of regulator derivatives with hybrid DmpR/XylR A-domains reveals that residues 110 to 186 are key determinants that distinguish the effector profiles of DmpR and XylR. Moreover, the properties of some mosaic DmpR/XylR derivatives reveal that high-affinity aromatic effector binding can be completely uncoupled from the ability to promote transcription. Hence, novel aromatic binding properties will only be translated into functional transcriptional activation if effector binding also triggers release of interdomain repression.

Amino Acid Sequence↗
PubMed1987

Translation of an mRNA in rat L6 muscle cells is regulated within the cell cycle.

In muscle cells two populations of mRNA are present in the cytoplasm. The majority of mRNA is associated with ribosomes and active in protein synthesis. A small population of cytoplasmic mRNA occur as free mRNA-protein complex and is not associated with ribosomes. This apparently repressed population of mRNA from rat L6 myoblast cells was used to construct a cDNA library. Radioactively labeled cDNA preparations of polysomal and free (or repressed) mRNA populations showed that at least ten recombinant clones preferentially annealed to the cDNA from repressed mRNA. One of these clones was extensively studied. The DNA from a recombinant plasmid D12 hybridized to a 1.3-kb poly(A)-rich mRNA. In proliferating myoblast cells, the 1.3-kb mRNA was more abundant in the polysomal fraction and mostly free in the non-dividing myotubes. In contrast to this mRNA, 90% of alpha and beta actin mRNAs were translated in both myoblasts and myotubes. Further analysis of distribution of the 1.3-kb RNA in the polysomal (active) and free (repressed) fractions in fusion-arrested postmitotic myotubes suggested that fusion of myoblasts was not necessary for the control of translation of this mRNA. Withdrawal of muscle cells from the cell cycle appeared to be involved in regulating translation of this mRNA. The presence of this mRNA was not, however, limited to muscle cells. This mRNA was also present in the repressed state in rat liver and kidney cells. These results, therefore, suggest that the 1.3-kb mRNA is probably translated during a particular phase of the cell cycle and is not translated in terminally differentiated non-dividing cells. Messenger RNA homologous to the 600-base-pair insert of the recombinant plasmid D12 was isolated by hybrid selection procedure from both polysomal mRNA of myoblasts and free mRNA of myotubes. Translation of the hybrid selected mRNAs from both myoblasts and myotubes in rabbit reticulocyte lysate cell-free system synthesized a 40-kDa polypeptide. These results suggest that the repressed population of 1.3-kb mRNA can be translated in vitro. The hybridization pattern of DNA from the recombinant plasmid D12 with rat genomic DNA suggested that the 1.3-kb mRNA is derived from moderately repetitive rat DNA with a repetition frequency of approximately 100 copies per haploid genome.

Actins↗
PubMed1997

Coupling of cell division to cell growth by translational control of the G1 cyclin CLN3 in yeast.

The eukaryotic cell cycle is driven by a cascade of cyclins and kinase partners including the G1 cyclin Cln3p in yeast. As the first step in this cascade, Cln3p is uniquely positioned to determine the critical growth-rate threshold for division. To analyze factors regulating CLN3 expression, we identified a short upstream open reading frame (uORF) in the 5' leader of CLN3 mRNA as a translational control element. This control element is critical for the growth-dependent regulation of Cln3p synthesis because it specifically represses CLN3 expression during conditions of diminished protein synthesis or slow growth. Inactivation of the uORF accelerates the completion of Start and entry into the cell cycle suggesting that translational regulation of CLN3 provides a mechanism coupling cell growth and division.

Antifungal Agents↗
PubMed1989

Mode of expression of the positive regulatory genes PHO2 and PHO4 of the phosphatase regulon in Saccharomyces cerevisiae.

The mode of expression was investigated for two positive regulatory genes, PHO2 and PHO4, whose products are indispensable for the transcriptional control of the structural genes of repressible acid phosphatase and the inorganic phosphate (Pi) transport system in Saccharomyces cerevisiae. Northern analysis of poly(A)+ RNA of the wildtype and the pho regulatory mutants with PHO4 DNA as hybridization probe and expressional analysis of a pho4'-'lacZ fused gene on a YEp plasmid revealed that PHO4 is expressed at a low level, constitutively, and independently of the PHO regulatory system and Pi in the medium. Similar analyses with PHO2 DNA indicated that PHO2 is expressed at an even lower level than PHO4, and is repressed by Pi and by the active PHO2 product, possibly at the translational level, while retaining a substantial level of basal activity.

Acid Phosphatase↗
PubMed1990

Mutational and functional analysis of the korA and korB gene products of Streptomyces plasmid pIJ101.

The korA and korB loci of Streptomyces lividans plasmid pIJ101 have previously been shown to control expression of the pIJ101 tra (formerly kilA) and kilB genes at the transcriptional level. We show here that mutations in translational open reading frames (ORFs) that map within the kor loci abolish repression of the S. lividans lac gene directed by the tra and kilB promoters. Introduction of the korA and korB ORFs into Escherichia coli maxicells under control of an E. coli promoter gave rise to 31 kDa and 10 kDa proteins that correspond in size to the products expected from the sequences of the respective ORFs; these proteins controlled transcription from the pIJ101 tra and kilB promoters in the E. coli host. Mutations that affected the KorA or KorB phenotype altered the structure of, or eliminated, the protein products of the korA and korB ORFs, further demonstrating that these ORFs encode the functional repressors of the pIJ101 kil/kor gene system.

Bacterial Proteins↗
PubMed1980

Immunoglobulin expression on theta-positive leukemic cells in AKR/J mice.

The expression of surface immunoglobulin was studied on cells of theta-positive AKR leukemia during repeated weekly passages of ascitic cells. It could be shown that the percentage of Ig-positive cells varied considerably (0-25%) and that this was accompanied by variations in the expression of theta-antigen on the cell surface. This was interpreted as repression and derepression of genes coding for surface antigen possibly at the translational level.

Animals↗
PubMed2006

Gene expression associated with compatible viral diseases in grapevine cultivars.

Viral diseases affect grapevine cultures without inducing any resistance response. Thus, these plants develop systemic diseases and are chronically infected. Molecular events associated with viral compatible infections responsible for disease establishment and symptoms development are poorly understood. In this study, we surveyed viral infection in grapevines at a transcriptional level. Gene expression in the Vitis vinifera red wine cultivars Carménère and Cabernet-Sauvignon naturally infected with GLRaV-3 were evaluated using a genome-wide expression profiling with the Vitis vinifera GeneChip from Affymetrix. We describe numerous genes that are induced or repressed in viral infected grapevines leaves. Changes in gene expression involved a wide spectrum of biological functions, including processes of translation and protein targeting, metabolism, transport, and cell defense. Considering cellular localization, the membrane and endomembrane systems appeared with the highest number of induced genes, while chloroplastic genes were mostly repressed. As most induced genes associated with the membranous system are involved in transport, the possible effect of virus in this process is discussed. Responses of both cultivars are analyzed and the results are compared with published data from other species. This is the first study of global gene profiling in grapevine in response to viral infections using DNA microarray.

Closteroviridae↗
PubMed1992

Expression of only one of two types of mRNA transcribed from the serine dehydratase gene is repressed in hepatoma cells.

The expressions of mRNA for serine dehydratase in H4IIE, HTC, and HepG2 hepatoma cells were investigated. Of the two types of mRNA transcribed from the single copy of the rat serine dehydratase gene, expression of only that encoding 35 kDa serine dehydratase is repressed in these cells. The other type coding the 8.9 kDa truncated translation product is expressed at a similar level to that in hepatocytes in primary culture and is not under hormonal control.

Alternative Splicing↗
PubMed2002

Distinct functional role of Hepatitis C virus core protein on NF-kappaB regulation is linked to genomic variation.

Hepatitis C virus (HCV) often causes a prolonged and persistent infection. Sequence divergence in the HCV genome indicates several genotypes and a series of subtypes for this virus. The core protein of HCV has many intriguing functional properties and is implicated as a factor in virus mediated pathogenesis. Nuclear factor kappaB (NF-kappaB), a transcription factor, responds to inflammatory signals, activates the expression of inflammatory mediators, and plays a role in cell proliferation process. In this study, we have investigated NF-kappaB regulation by HCV core protein cloned from three isolates of different genotypes. Our results suggest that core protein from HCV genotype 1a represses NF-kappaB activation, unlike two other core genomic regions from HCV genotype 1b (BK or Taiwan). However, missense mutations in positions (K(9) to R or N(11) to T) of HCV genotype 1a relieve repression of NF-kappaB regulation by core protein. Interestingly, in vitro translation studies suggested that amino acid substitution at position 11 (N-->T) in HCV genotype 1a generated a primary protein product of approximately 17 kDa, smaller than the major approximately 21 kDa protein band apparent in the parental sequence or with one carrying mutation at amino acid position 9 (K-->R). However, the approximately 17 kDa protein did not appear to be involved in NF-kappaB regulation. Taken together, our present data suggest that genomic variation in the core protein determines a distinct functional regulation of NF-kappaB, which may modulate immunnoregulatory molecules early in viral infection.

Amino Acid Sequence↗
PubMed1979

Biotinyl 5'-adenylate: corepressor role in the regulation of the biotin genes of Escherichia coli K-12.

A DNA filter-binding technique was used to study the interaction of the biotin repressor and operator site. From a biotin saturation curve, the concentration for half-maximal binding (K0.5) was calculated to be 1 microM. However, in a similar study with the in vitro coupled transcription-translation system in which biotin served as the corepressor, the K0.5 for repression was 7.1 nM. This marked difference of over 2 orders of magnitude was attributed to the activation of biotin by the partially purified repressor preparation in the in vitro system. The activated product formed from biotin, ATP, and repressor preparation was identified as biotinyl 5'-adenylate by paper chromatography and hydroxamic acid formation. Synthetic biotinyl 5'-adenylate was as effective as biotin in the in vitro system (K0.5, 10 nM) and much more effective than biotin in the DNA-binding assay (K0.5 1.1 nM versus 1 microM). These studies indicate that biotinyl 5'-adenylate has a more direct role in the regulation of the biotin genes than does biotin per se.

Adenosine Monophosphate↗
PubMed1992

Synthesis of the early light-inducible protein is controlled by blue light and related to light stress.

The early light-inducible proteins (ELIPs) are expressed in developing plants in the first hours of the greening process. Here we report that strong light causing photoinhibition of photosynthesis also induces ELIP transcription and accumulation of the protein in mature green pea plants. Accumulation of ELIP transcript is induced in plants exposed to light intensities above 500 E/m2.s (E, einstein) and is maximal at approximately 1500 E/m2.s. The ELIP mRNA level increases in correlation with the degree of photoinhibition. The increase in ELIP level in the thylakoid membranes parallels the decrease in the amount of D1 protein of the photosystem II reaction center. Examination of ELIP induction as a function of light quality demonstrates that ELIP transcription is specifically induced by blue (410-480 nm) but not by red or far-red light. The level of blue light-induced ELIP transcript is significantly repressed by low-intensity red light. However, the accumulation of ELIP translation product is related to the total amount of blue and red light energy absorbed.

Journal Article↗
PubMed2002

Regulation of histone deacetylase 2 by protein kinase CK2.

Histone deacetylase 2 (HDAC2) is a member of a large family of enzymes that alter gene expression by catalyzing the removal of acetyl groups from core histones. Originally isolated as a transcriptional co-repressor, HDAC2 possesses extensive amino acid sequence homology to HDAC1 (the founding member and most extensively studied HDAC enzyme). Because of this high degree of sequence similarity between HDAC1 and HDAC2, coupled with the fact that the two always co-exist in the same complexes, it is difficult to assess whether different properties exist between these two proteins. We report here that HDAC2 is a phosphoprotein similar to HDAC1. In addition, like HDAC1, the phospho-acceptor sites in HDAC2 are located in the C-terminal portion of the protein. However, unlike HDAC1, which can be phosphorylated by protein kinase CK2, cAMP-dependent protein kinase, and protein kinase G, HDAC2 is phosphorylated uniquely by protein kinase CK2 in vitro. Studies using unfractionated cell extracts with CK2 inhibitors suggest that protein kinase CK2 is the major source of HDAC2 kinase. Finally, and perhaps most interesting, HDAC2 phosphorylation promotes enzymatic activity, selectively regulates complex formation, but has no effect on transcriptional repression. Together, our data indicate that like many HDACs, HDAC2 is regulated by post-translational modification, particularly phosphorylation. Furthermore, we demonstrate for the first time that there are similarities and differences in the regulation of HDAC1 and HDAC2 by phosphorylation.

Amino Acid Sequence↗
PubMed2002

Novel leader exons of the cyclic adenosine 3',5'-monophosphate response element modulator (CREM) gene, transcribed from promoters P3 and P4, are highly testis-specific in primates.

Testicular expression of CREM is essential for spermatogenesis in the mouse. From a monkey testis cDNA library we isolated a CREM transcript isoform with a novel 5' exon theta2 which provides at its 3'-end an in-frame ATG to the downstream reading frame. 5'-RACE on human testis cDNA indicated that exon theta2 is > or = 113 bp in size. Moreover, a second novel leader exon, theta1, of > or = 289 bp was identified and encodes a putative open reading frame of 26 amino acids. In-vitro translation and cellular expression of CREM-theta1 and CREM-theta2 splice variants cloned from human testis yielded not only full length proteins but also shorter repressor products resulting from downstream translation initiation. Upon co-transfection, products of CREM-theta2 cDNA repressed protein kinase A-induced activation of a CRE-driven reporter construct. RT-PCR analysis of primate tissues for CREM-theta2 transcripts showed abundant expression in the testis and very low levels or absence from all other tissues tested. CREM-theta1 mRNA was exclusively expressed in the testis. Promoters P3 and P4, flanking exons theta1 and theta2, were cloned and found to be non-responsive to protein kinase A in transfection assays. Furthermore, we show differential activation of P1, P3 and P4 during mouse postnatal testicular development, suggesting cell- and stage-specific regulatory mechanisms for these CREM promoters.

Alternative Splicing↗