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PubMed2005

Extensive 3' modification of plant small RNAs is modulated by helper component-proteinase expression.

RNA silencing is an evolutionarily conserved process in eukaryotes that represses gene expression by using 21- to 24-nt guide RNAs to mediate mRNA cleavage or translational inhibition. Plants have two distinct groups of silencing-associated small RNAs (smRNAs): the micro RNAs (miRNAs) and the small interfering RNAs (siRNAs). A recent report by Yu et al. [Yu, B., Yang, Z., Li, J., Minakhina, S., Yang, M., Padgett, R. W., Steward, R. & Chen, X. (2005) Science 307, 932-935] has shown that plant miRNAs are modified at their 3' termini with a methyl group. Here, we show that a large fraction of all silencing-associated smRNAs in tobacco are modified; this modification occurs on the 2' hydroxyl of the terminal ribose and significantly reduces the cloning efficiency of these modified smRNAs. Expression of the strong silencing suppressor P1/helper-component proteinase results in a marked decrease in the 3'-terminal modification of viral siRNAs but does not significantly affect the modification of endogenous miRNAs and 24-nt siRNAs. The differential modification mediated by helper-component proteinase expression implies that exogenous and endogenous smRNAs are processed through independent pathways that are isolated by subcellular compartmentalization and/or the association with distinct Dicer complexes. The degree of terminal modification may play an important role in regulating the extent to which primary smRNA signals can be amplified by RNA-dependent RNA polymerases.

Gene Expression Regulation, Plant↗
PubMed2005

HER-2/neu represses the metastasis suppressor RECK via ERK and Sp transcription factors to promote cell invasion.

Matrix metalloproteinase (MMP) inhibitory proteins may negatively regulate MMP activity to suppress tumor metastasis. In this study, we demonstrate that the HER-2/neu oncogene inhibits the expression of the MMP inhibitor RECK to promote cell invasion. RECK was inhibited via transcriptional repression in B104-1-1 cells, which express constitutively active HER-2/neu. Overexpression of HER-2/neu in NIH/3T3 or HaCaT cells also suppressed RECK expression. Deletion and mutation assays showed that HER-2/neu repressed RECK via the Sp1-binding site localized in the -82/-71 region from the translational start site. DNA affinity precipitation and chromatin immunoprecipitation assays indicated that binding of Sp1 and Sp3 to this consensus site was increased in B104-1-1 cells. We also found that HER-2/neu inhibited RECK via the ERK signaling pathway. Sp1 proteins phosphorylated at Thr453 and Thr739 by ERK bound preferentially to the RECK promoter, and this binding was reversed by HER-2/neu and ERK inhibitors. Furthermore, our data indicate that HER-2/neu obviously increased HDAC1 binding to the Sp1-binding site localized in the -82/-71 region of the RECK promoter. The histone deacetylase inhibitor trichostatin A reversed HER-2/neu-induced inhibition of RECK. HER-2/neu activation was associated with increased MMP-9 secretion and activation. Re-expression of RECK in HER-2/neu-overexpressing cells inhibited MMP-9 secretion and cell invasion. Taken together, our results suggest that HER-2/neu induces the binding of Sp proteins and HDAC1 to the RECK promoter to inhibit RECK expression and to promote cell invasion. Restoration of RECK provides a novel strategy for the inhibition of HER-2/neu-induced metastasis.

Animals↗
PubMed1998

Regulation of Drosophila Adh promoter switching by an initiator-targeted repression mechanism.

The stage-specific expression of the Drosophila alcohol dehydrogenase (Adh) gene is achieved through the alternate activation of two tandem promoters. The proximal promoter is active primarily during late embryonic development and early larval stages, while the distal promoter is active in late third instar larvae and adults. Here, we provide evidence that this Adh promoter switch is regulated by a zinc finger repressor protein (AEF-1) that is expressed predominantly in adult flies and targets the initiator region of the proximal promoter. We propose that AEF-1 plays a critical role in Adh promoter switching by blocking interactions between a component of the general transcription machinery and the initiator region of the proximal promoter.

Alcohol Dehydrogenase↗
PubMed1997

Inhibition of the multiple antibiotic resistance (mar) operon in Escherichia coli by antisense DNA analogs.

The multiple antibiotic resistance operon (marORAB) in Escherichia coli controls intrinsic susceptibility and resistance to multiple, structurally different antibiotics and other noxious agents. A plasmid construct with marA cloned in the antisense direction reduced LacZ expression from a constitutively expressed marA::lacZ translational fusion and inhibited the induced expression of LacZ in cells bearing the wild-type repressed fusion. The marA antisense construction also decreased the multiple antibiotic resistance of a Mar mutant. Two antisense phosphorothioate oligonucleotides, one targeted to marO and the other targeted to marA of the mar operon, introduced by heat shock or electroporation reduced LacZ expression in the strain having the marA::lacZ fusion. One antisense oligonucleotide, tested against a Mar mutant of E. coli ML308-225, increased the bactericidal activity of norfloxacin. These studies demonstrate the efficacy of exogenously delivered antisense oligonucleotides targeted to the marRAB operon in inhibiting expression of this chromosomal regulatory locus.

Cloning, Molecular↗
PubMed1991

Psychoanalytic interpretation of the Rorschach: do we have better hieroglyphics?

Schafer (1954) advanced the "Psychoanalytic Interpretation in Rorschach Testing" and asserted that thoughtful interpretation involved more than translating hieroglyphics or scores. In this book, he presented his thesis by describing four defensive styles (repression, denial, projective, and obsessive-compulsive) at various levels of severity of psychopathology. To investigate whether the Structural Summary data from Exner's (1986) Comprehensive System, with its improved reliability and validity and additional scores, allow one to make similar distinctions among the types of defense and severity of disturbance, we rescored the Schafer records. The results of this conservative test of Exner's system suggest that (a) the Comprehensive System reliably distinguishes the repressive style from the other styles, and (b) scores alone may provide adequate measures of severity of disturbance even with form quality excluded. We concluded that Rorschach scores must be understood as complex products of multiple psychological operations and may correspond to different subjective experiences in various contexts.

Defense Mechanisms↗
PubMed1999

[Sequence analysis of the mutated AOX2 promoter region in the Pichia pastoris].

Spontaneous revertants of the AOX1-defective P. pastoris strain have been isolated, which were identified as phenotypically utilize methanol to grow as the wild type. The promoter region of the AOX2 gene from the revertant has been obtained by PCR amplification, and the DNA fragment is 1022 base pair in size. By the analysis of sequencing result and compared with the AOX2 gene sequences recorded in Gene Bank, two point mutations which at positions of -529 and -255(relative to the translation initiation codon) respectively, have been found. Since the positions are located in the AOX2 upstream repression sequences, the mutations may act interfere the repressor to combine with the functional sequences, and increase transcriptional activity. The above result implicated that the P. pastoris' ability to utilize methanol could be increased through modification the upper stream transcriptional regulation region in the AOX2 gene.

Alcohol Oxidoreductases↗
PubMed1987

Gene induction and repression by salt treatment in roots of the salinity-sensitive Chinese Spring wheat and the salinity-tolerant Chinese Spring x Elytrigia elongata amphiploid.

An artificial amphiploid from a cross between salinity-sensitive bread wheat cultivar Chinese Spring and highly tolerant Elytrigia elongata (Host) Nevski (= Agropyron elongatum Host) shows enhanced salinity tolerance relative to Chinese Spring. Poly(A)(+) RNA was isolated from roots, expanding leaves, and old leaves from amphiploid and Chinese Spring plants prior to and after acclimation to high levels of NaCl in solution cultures. Two-dimensional gel electrophoresis of the in vitro translation products was used to compare these mRNA populations. The amphiploid had 10 mRNA species induced or enhanced and 8 species repressed in root tissue during acclimation to saline growth conditions. These 18 transcripts affected by salt treatment were also detected in wheat roots, but only 4 of these were similarly regulated. In Chinese Spring the acclimation to saline stress resulted in a marked change in the level of expression of 34 transcripts in root tissue; of these, 26 were detected in the amphiploid and only 6 were regulated as in the amphiploid. No differences were seen in gene expression between salt-treated and control plants in leaves and meristematic crowns and unexpanded leaves of the amphiploid.

Journal Article↗
PubMed1999

The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans by blocking LIN-14 protein synthesis after the initiation of translation.

lin-4 encodes a small RNA that is complementary to sequences in the 3' untranslated region (UTR) of lin-14 mRNA and that acts to developmentally repress the accumulation of LIN-14 protein. This repression is essential for the proper timing of numerous events of Caenorhabditis elegans larval development. We have investigated the mechanism of lin-4 RNA action by examining the fate of lin-14 mRNA in vivo during the time that lin-4 RNA is expressed. Our results indicate that the rate of synthesis of lin-14 mRNA, its state of polyadenylation, its abundance in the cytoplasmic fraction, and its polysomal sedimentation profile do not change in response to the accumulation of lin-4 RNA. Our results indicate that association of lin-4 RNA with the 3' UTR of lin-14 mRNA permits normal biogenesis of lin-14 mRNA, and normal translational initiation, but inhibits step(s) thereafter, such as translational elongation and/or the release of stable LIN-14 protein.

3' Untranslated Regions↗
PubMed1999

Dual roles of p82, the clam CPEB homolog, in cytoplasmic polyadenylation and translational masking.

In the transcriptionally inert maturing oocyte and early embryo, control of gene expression is largely mediated by regulated changes in translational activity of maternal mRNAs. Some mRNAs are activated in response to poly(A) tail lengthening; in other cases activation results from de-repression of the inactive or masked mRNA. The 3' UTR cis-acting elements that direct these changes are defined, principally in Xenopus and mouse, and the study of their trans-acting binding factors is just beginning to shed light on the mechanism and regulation of cytoplasmic polyadenylation and translational masking. In the marine invertebrate, Spisula solidissima, the timing of activation of three abundant mRNAs (encoding cyclin A and B and the small subunit of ribonucleotide reductase, RR) in fertilized oocytes correlates with their cytoplasmic polyadenylation. However, in vitro, mRNA-specific unmasking occurs in the absence of polyadenylation. In Walker et al. (in this issue) we showed that p82, a protein defined as selectively binding the 3' UTR masking elements, is a homolog of Xenopus CPEB (cytoplasmic polyadenylation element binding protein). In functional studies reported here, the elements that support polyadenylation in clam egg lysates include multiple U-rich CPE-like motifs as well as the nuclear polyadenylation signal AAUAAA. This represents the first detailed analysis of invertebrate cis-acting cytoplasmic polyadenylation signals. Polyadenylation activity correlates with p82 binding in wild-type and CPE-mutant RR 3' UTR RNAs. Moreover, since anti-p82 antibodies specifically neutralize polyadenylation in egg lysates, we conclude that clam p82 is a functional homolog of Xenopus CPEB, and plays a positive role in polyadenylation. Anti-p82 antibodies also result in specific translational activation of masked mRNAs in oocyte lysates, lending support to our original model of clam p82 as a translational repressor. We propose therefore that clam p82/CPEB has dual functions in masking and cytoplasmic polyadenylation.

3' Untranslated Regions↗
PubMed2006

Novel HESX1 mutations associated with a life-threatening neonatal phenotype, pituitary aplasia, but normally located posterior pituitary and no optic nerve abnormalities.

CONTEXT: Hesx1 is one of the earliest homeodomain transcription factors expressed during pituitary development. Very few HESX1 mutations have been identified in humans; although in those cases the disease phenotype shows considerable variability, all but one of the patients display an ectopic posterior pituitary and/or optic nerve abnormalities. OBJECTIVE: The objectives of the study were to describe the complex phenotype associated with the panhypopituitarism of two unrelated Italian patients who, at birth, presented with hypoglycemic seizures and respiratory distress complicated by shock, in a familial context of neonatal death in one family and spontaneous miscarriage in both families and to identify the molecular basis of this unusual syndrome. MAIN OUTCOME MEASURES: Magnetic resonance imaging of the pituitary region, study of HESX1 gene and transcripts, and assessment of the ability of mutated HESX1 proteins to repress transcription were measured. RESULTS: Magnetic resonance imaging examination showed an anterior pituitary aplasia in a flat sella turcica and a normally located posterior pituitary in both patients. A constellation of extrapituitary developmental defects were found in the two patients, but without any optic nerve abnormalities. Sequencing of HESX1 exons and their flanking intronic regions revealed two different homozygous mutations. A frameshift (c.449_450delAC) was identified in one case, whereas the other patient carried a splice defect (c.357 + 2Tb > C) confirmed by the study of HESX1 transcripts. If translated, these mutations would lead to the synthesis of truncated proteins partly or entirely lacking the homeodomain, with no transcriptional repression, as shown by their inability to inhibit PROP1 activity. CONCLUSIONS: These observations reveal two novel HESX1 mutations in a so-far-undescribed disease phenotype characterized by a life-threatening neonatal condition associated with anterior pituitary aplasia, in the absence of ectopic posterior pituitary and optic nerve abnormalities, two features classically associated with HESX1 defects.

Cells, Cultured↗
PubMed1994

Catabolite repression of the Bacillus subtilis xyl operon involves a cis element functional in the context of an unrelated sequence, and glucose exerts additional xylR-dependent repression.

Catabolite repression (CR) of xylose utilization by Bacillus subtilis involves a 14-bp cis-acting element (CRE) located in the translated region of the gene encoding xylose isomerase (xylA). Mutations of CRE making it more similar to a previously proposed consensus element lead to increased CR exerted by glucose, fructose, and glycerol. Fusion of CRE to an unrelated, constitutive promoter confers CR to beta-galactosidase expression directed by that promoter. This result demonstrates that CRE can function independently of sequence context and suggests that it is indeed a generally active cis element for CR. In contrast to the other carbon sources studied here, glucose leads to an additional repression of xylA expression, which is independent of CRE and is not found when CRE is fused to the unrelated promoter. This repression requires a functional xylR encoding Xyl repressor and is dependent on the concentrations of glucose and the inducer xylose in the culture broth. Potential mechanisms for this glucose-specific repression are discussed.

Aldose-Ketose Isomerases↗
PubMed1981

Translational regulation: identification of the site on bacteriophage T4 rIIB mRNA recognized by the regA gene function.

The bacteriophage T4 gene regA encodes a protein that diminishes the expression of many unlinked early T4 genes. Previous work demonstrated that regA-mediated repression occurs after transcription. We report here on the identification of the target site on one regA-sensitive mRNA, the message encoding the phage T4 rIIB protein. The target for regA-mediated action overlaps the translational initiation domain of the rIIB messenger. The regA protein may be a repressor that operates translationally on a significant and interesting set of early phage T4 mRNAs.

Base Sequence↗
PubMed2004

Repression of G0/G1 traverse in human fibroblasts exposed to low levels of ionizing radiation.

Quiescent cultures of human fibroblasts were exposed to levels of ionizing radiation sufficient to induce a transient growth delay, while causing only small decreases in long term clonogenicity. Following the mitogenic stimulation of damaged cells, cyclin D-associated kinase activity was induced to levels equivalent to those seen in control cultures. In addition, late G0/G1 E2F-dependent transcriptional and translational activity was observed in restimulated irradiated cells. However, cells became arrested prior to entry into S phase in a manner that paralleled the repression of cdk2-associated kinase activity. Cyclin A/cdk2-associated kinase activity was repressed in a biphasic manner following the irradiation of logarithmically growing cells. The initial rapid decline in activity to levels approximately 50% of those observed in control cultures occurred prior to increases in cellular levels of p21Cip1 protein, was not blocked by the addition of cycloheximide, and was not accompanied by alterations in cdk2 phosphotyrosine content. The subsequent repression to undetectable levels was coincident with the induction of p21Cip1 and was dependent on de novo protein synthesis. Only a subpopulation of cyclin A complexes were associated with p21Cip1 regardless of the magnitude of the repression of catalytic activity, although all cyclin A-cdk2-p21Cip1 complexes were inactive. These data suggest that temporally and functionally distinct mechanisms mediate the repression of cyclin-cdk activity in damaged cells. In addition, we present evidence that irradiated cells are competent to traverse S phase and arrest in G2 in the complete absence of cdk2-associated kinase activity.

Cell Line↗
PubMed1984

Toxicity of an overproduced foreign gene product in Escherichia coli and its use in plasmid vectors for the selection of transcription terminators.

A rat insulin gene which was fused to Escherichia coli signals for the initiation of translation could not be retained when expressed from the strong rrnB ribosomal RNA promoters or an induced trp/lac (= tac) hybrid promoter. When the latter promoter was repressed by transformation into a lac-repressor-overproducing strain, the insulin gene fragment could be retained. Upon induction of the promoter with isopropyl-beta-D-galactosidase the growth rate of the cells was reduced, and in most cases the cells subsequently lysed. Deletion of the translational initiation signals, changing the reading frame, or insertion of an efficient transcription terminator between the promoter and the rat insulin gene each permitted retention of the fragment. The first two observations indicate that overproduction of the specific polypeptide, and not of the RNA, is detrimental to the cell. The third finding has been exploited for the testing and selection of transcription terminators. The rpoC terminator, which is located distal to the rplJL /rpoBC operon, has been shown to terminate transcripts from the rrnB promoters. It was also shown that the putative rrnB terminators, T1 and T2, each function separately in vivo.

Animals↗
PubMed1984

Repression of the synthesis of exocellular and intracellular proteinases in Bacillus megaterium.

The synthesis of exocellular proteinase decreases with increasing concentration of amino acids in the growth medium. After removal of amino acids the enzyme synthesis is gradually restored to normal values. The presence of inhibitors of transcription (actinomycin D) or translation (chloramphenicol) blocks the restoration of enzyme synthesis. No active or inactive precursors of the exocellular enzyme could be detected in the cell. It is likely that the enzyme synthesis is regulated by amino acids at the level of specific mRNA synthesis rather than at the translation level or at the level of secretion. The activity of the enzyme that has already been secreted to the external medium is partially inhibited by amino acids. The periplasmic proteinase is repressed by amino acids to the same extent as the exocellular enzyme. The content of the enzyme(s) inside the protoplast is also decreased during growth in the presence of amino acids.

Amino Acids↗
PubMed1999

Interactive regulatory pathways control virulence determinant production and stability in response to environmental conditions in Staphylococcus aureus.

The accessory gene regulator (agr) and staphylococcal accessory regulator (sar) loci are important regulators of toxin production in Staphylococcus aureus. In this study we examined how environmental conditions degree of aeration and salt concentration - affect the transcription and translation of mRNAs for alpha-haemolysin (Hla) and serine protease (Ssp) via these pathways and influence the stability of these proteins. Using Northern analysis, we have confirmed earlier observations that sarA is involved in the upregulation of RNAIII, the effector molecule encoded by the agr locus. However, this effect was abolished in highly aerated cultures. While sarA does appear to have an up-regulatory effect on hla transcription that is independent of agr, we propose that the PC1839 (sarA) mutant produces less alpha-haemolysin activity mainly as a result of post-translational inactivation by proteases. The most obvious phenotypic feature of PC1839 (sarA) is the upregulation of proteases. In this study we show that ssp is repressed by SarA at the transcriptional level. Western analysis using an anti-alpha-haemolysin antibody identified a major breakdown product that is only present in the supernatant of strains that are overexpressing serine protease. We have also confirmed that agr exerts a significant regulatory influence on hla at the level of translation, as well as transcription. Finally, the addition of salt upregulates ssp transcription and dramatically downregulates transcription of hla, and is an example of an environmental parameter that affects toxin production independently of agr and sarA. How environmental signals are transduced to control alpha-haemolysin and serine protease production, activity and stability at multiple levels are discussed.

Bacterial Proteins↗
PubMed2005

A feedforward loop motif in transcriptional regulation: induction and repression.

We study the dynamical behavior of a unit of three positive transcriptional regulators which occurs frequently in biological networks of yeast and bacteria as a feedforward loop. We investigate numerically a set of reactions incorporating the basic features of transcription and translation. We determine (i) how the feedforward loop motif functions as a computational element such as an AND gate in the presence of stochastic fluctuations, and (ii) the robustness of the motif when transcription at the primary level is suddenly repressed. We highlight the effective time-scales which underlie both of these aspects of the feedforward loop motif. We show how threshold behavior of the motif output arises as a function of the number of external inducers as well as the time over which the inducer acts. We discuss how individual cell behavior can deviate significantly from average behavior, due to intrinsic fluctuations in the small number of molecules present in a cell.

Algorithms↗