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PubMed1996

The mec-8 gene of C. elegans encodes a protein with two RNA recognition motifs and regulates alternative splicing of unc-52 transcripts.

Mutations in the mec-8 gene of Caenorhabditis elegans were previously shown to affect the functions of body wall muscle and mechanosensory and chemosensory neurons. Mutations in mec-8 also strongly enhance the mutant phenotype of specific mutations in unc-52, a gene that encodes, via alternative splicing of pre-mRNA, a set of basement membrane proteins, homologs of perlecan, that are important for body wall muscle assembly and attachment to basement membrane, hypodermis and cuticle. We have cloned mec-8 and found that it encodes a protein with two RNA recognition motifs, characteristic of RNA binding proteins. We have used reverse transcription-PCR and RNase protection experiments to show that mec-8 regulates the accumulation of a specific subset of alternatively spliced unc-52 transcripts. We have also shown with antibodies to UNC-52 that mec-8 affects the abundance of a subset of UNC-52 isoforms. We propose that mec-8 encodes a trans-acting factor that regulates the alternative splicing of the pre-mRNA of unc-52 and one or more additional genes that affect mechanosensory and chemosensory neuron function.

Alternative Splicing↗

PubMed1997

Cyclin A message stability varies with the cell cycle.

Progression through the cell cycle in somatic eukaryotic cells is regulated by variations in the levels of cyclin proteins. These protein levels are in turn regulated by cyclical oscillations in their mRNA levels. We show here that regulation of RNA stability plays a role in the mechanisms underlying cell cycle progression. Both cyclin A and B1 messages are expressed at high levels in G2-M and at low levels in early G1. The half-lives of their messages mirror this pattern, long in G2-M (>8 h) and short in early G1 (1-2 h). However, there is evidence of specificity to these changes, because the cyclin A message becomes stable at the G1-S boundary, whereas the cyclin B1 message is unstable until later in S phase. Furthermore, although cyclin B1 mRNA levels are lowered after irradiation because of enhanced instability, cyclin A mRNA levels and message stability are unaffected by irradiation. Additional evidence of specificity was found in an analysis of cyclin E mRNA stability, which remains constant through the cell cycle, although the cyclin E message displays cell cycle-dependent changes in expression. These studies suggest that specific alterations in RNA stability are an important component in regulating the expression of cyclins A and B1 and hence in controlling the cell cycle.

Blotting, Northern↗

PubMed1998

Alternative RNA processing--its role in regulating expression of calcitonin/calcitonin gene-related peptide.

The calcitonin/calcitonin gene-related peptide (CT/CGRP) gene is one of the earliest studied examples of alternative RNA processing. The regulatory mechanisms controlling this event are poorly understood. We have identified and characterized an intron element residing in intron 4 of the human CT/CGRP gene. This intron element functions to enhance polyadenylation of an embedded alternative 3'-terminal exon within the CT/CGRP gene and is potentially involved in tissue-specific regulation of CT/CGRP RNA processing.

Alternative Splicing↗

PubMed2005

The Drosophila dosage compensation complex binds to polytene chromosomes independently of developmental changes in transcription.

In Drosophila, the dosage compensation complex (DCC) mediates upregulation of transcription from the single male X chromosome. Despite coating the polytene male X, the DCC pattern looks discontinuous and probably reflects DCC dynamic associations with genes active at a given moment of development in a salivary gland. To test this hypothesis, we compared binding patterns of the DCC and of the elongating form of RNA polymerase II (PolIIo). We found that, unlike PolIIo, the DCC demonstrates a stable banded pattern throughout larval development and escapes binding to a subset of transcriptionally active areas, including developmental puffs. Moreover, these proteins are not completely colocalized at the electron microscopy level. These data combined imply that simple recognition of PolII machinery or of general features of active chromatin is either insufficient or not involved in DCC recruitment to its targets. We propose that DCC-mediated site-specific upregulation of transcription is not the fate of all active X-linked genes in males. Additionally, we found that DCC subunit MLE associates dynamically with developmental and heat-shock-induced puffs and, surprisingly, with those developing within DCC-devoid regions of the male X, thus resembling the PolIIo pattern. These data imply that, independently of other MSL proteins, the RNA-helicase MLE might participate in general transcriptional regulation or RNA processing.

Animals↗

PubMed1996

A temperature-sensitive trpS mutation interferes with trp RNA-binding attenuation protein (TRAP) regulation of trp gene expression in Bacillus subtilis.

In Bacillus subtilis, the tryptophan-activated trp RNA-binding attenuation protein (TRAP) regulates expression of the seven tryptophan biosynthetic genes by binding to specific repeat sequences in the transcripts of the trp operon and of the folate operon, the operon containing trpG. Steinberg observed that strains containing a temperature-sensitive mutant form of tryptophanyl-tRNA synthetase, encoded by the trpS1 allele, produced elevated levels of the tryptophan pathway enzymes, when grown at high temperatures in the presence of excess L-tryptophan (W. Steinberg, J. Bacteriol. 117:1023-1034, 1974). We have confirmed this observation and have shown that expression of two reporter gene fusions, trpE'-'lacZ and trpG'-'lacZ, is also increased under these conditions. Deletion of the terminator or antiterminator RNA secondary structure involved in TRAP regulation of trp operon expression eliminated the trpS1 effect, suggesting that temperature-sensitive expression was mediated by the TRAP protein. Analysis of expression of mtrB, the gene encoding the TRAP subunit, both by examination of a lacZ translational fusion and by measuring the intracellular levels of TRAP by immunoblotting, indicated that the trpS1-induced increase in trp gene expression was not due to inhibition of mtrB expression or to alteration of the amount of TRAP present per cell. Increasing the cellular level of TRAP by overexpressing mtrB partially counteracted the trpS1 effect, demonstrating that active TRAP was limiting in the trpS1 mutant. We also showed that elevated trp operon expression was not due to increased transcription initiation at the upstream aroF promoter, a promoter that also contributes to trp operon expression. We postulate that the increase in trp gene expression observed in the trpS1 mutant is due to the reduced availability of functional TRAP. This could result from inhibition of TRAP function by uncharged tRNA(Trp) molecules or by increased synthesis of some other transcript capable of binding and sequestering the TRAP regulatory protein.

Anthranilate Synthase↗

PubMed2002

Ribozyme termination of RNA transcripts down-regulate seed fatty acid genes in transgenic soybean.

We investigated whether termination of transcripts with a self-cleaving ribozyme can enhance nuclear retention and serve as a tool to decrease specific plant gene expression. Nuclear retention was first monitored in tobacco using the beta-glucuronidase gene terminated with either the 35S CaMV 3' untranslated sequence (UTR) or a cis-acting ribozyme. Northern blot analysis of nuclear RNA and total RNA, and in situ hybridizations showed that the ribozyme-terminated transcripts were preferentially retained in the nucleus of transgenic tobacco. Ribozyme-terminated transcripts were subsequently tested as a gene down-regulation strategy in soybean. The embryo-specific Delta-12 fatty acid desaturase FAD2-1 gene was targeted because its down-regulation elevates oleic acid content of seed storage lipids. Both ribozyme-terminated antisense and standard antisense constructs were capable of gene down-regulation, producing over 57% oleic acid compared with less than 18% in wild-type seed. Ribozyme termination cassettes were also constructed to evaluate sense transcripts for single gene down-regulation and the simultaneous down-regulation of two embryo-specific genes in soybean using a single promoter. Eight independent soybean transformants were screened that harboured standard plus sense or ribozyme terminated FAD2-1 cassette. Two of the eight ribozyme terminated transformants displayed oleic acids levels in the seed storage lipids of over 75%, while none of the standard plus sense FAD2-1 lines showed elevated oleic acid phenotypes. The dual constructs targeted FAD2-1 and the FatB gene encoding a palmitoyl-thioesterase. Five transgenic soybean lines harbouring the dual constructs had oleic acid levels, greater than 85%, and saturated fatty acids levels, less than 6%. Thus, ribozyme termination of transcripts can be utilized to specifically down-regulate endogenous gene expression in soybean.

3' Untranslated Regions↗

PubMed1989

Antidepressants regulate glucocorticoid receptor messenger RNA concentrations in primary neuronal cultures.

Increased cortisol secretion, caused by hyperactivity of the brain-pituitary-adrenal axis, and non-suppression of cortisol secretion following dexamethasone administration are two characteristics frequently associated with major depression or the depressed phase of bipolar illness. Antidepressants, irrespective of their selective inhibitory actions on the re-uptake of serotonin or of norepinephrine, modify glucocorticoid receptor messenger RNA concentrations in primary cultures of rat hypothalamic or amygdaloid neurons in a biphasic manner, with predominant stimulatory effects. This suggests a mechanism whereby antidepressants, by restoring the sensitivity of the limbic-hypothalamic system to glucocorticoid feedback inhibition, reverse the hyperactivity of the brain-pituitary-adrenal axis.

Amygdala↗

PubMed2006

RNA editing by ADAR2 is metabolically regulated in pancreatic islets and beta-cells.

RNA editing via the conversion of adenosine (A) to inosine (I) is catalyzed by two major families of adenosine deaminases acting on RNA (ADARs), ADAR1 and ADAR2. This genetic recoding process is known to play essential roles in the brain, due in part to changes in functional activities of edited neurotransmitter receptors and ion channels. Little is known, however, about the physiological regulation and function of A to I RNA editing in peripheral tissues and other biological processes. Here, we report that both ADAR1 and ADAR2 are expressed in the murine pancreatic islets, and ADAR2 is primarily localized in the islet endocrine cells. In contrast to ADAR1, ADAR2 transcripts in the pancreatic islets exhibit a nearly 2-fold increase in insulin-resistant mice chronically fed a high fat diet. Concurrent with this diet-induced metabolic stress, RNA editing in the islets is dramatically enhanced for the RNA transcripts encoding the ionotropic glutamate receptor subunit B. Moreover, ADAR2 protein expression is repressed in the islets under fuel deficiency condition during fasting, and this repression can be completely reversed by refeeding. We also show that, specifically in pancreatic beta-cell lines, not only the expression of ADAR2 but also the glutamate receptor subunit B editing and ADAR2 self-editing are markedly augmented in response to glucose at the physiological concentration for insulin secretion stimulation. Thus, RNA editing by ADAR2 in pancreatic islets and beta-cells is metabolically regulated by nutritional and energy status, suggesting that A to I RNA editing is most likely involved in the modulation of pancreatic islet and beta-cell function.

Adenosine Deaminase↗

PubMed1994

RNA transcription in axotomized dorsal root ganglion neurons.

Levels of RNA transcription were examined in L5 sensory ganglion neurons after unilateral crush injuries of the sciatic nerve using an in situ autoradiographic technique. Neuronal transcription increased in a biphasic pattern on the lesioned side within the first two weeks after injury. The timing and pattern of increases in transcription corresponded to previously reported increases RNA synthesis. The data demonstrate a dynamic regulation of RNA transcription in regenerating neuronal populations. This technique may prove to be useful in the study of factors controlling transcriptional activity in injured neurons.

Animals↗

PubMed2005

Role of Sam68 as an adaptor protein in signal transduction.

Sam68, the substrate of Src in mitosis, belongs to the family of RNA binding proteins. Sam68 contains consensus sequences to interact with other proteins via specific domains. Thus, Sam68 has various proline-rich sequences to interact with SH3 domain-containing proteins. Moreover, Sam68 also has a C-terminal domain rich in tyrosine residues that is a substrate for tyrosine kinases. Tyrosine phosphorylation of Sam68 promotes its interaction with SH2 containing proteins. The association of Sam68 with SH3 domain-containing proteins, and its tyrosine phosphorylation may negatively regulate its RNA binding activity. The presence of these consensus sequences to interact with different domains allows this protein to participate in signal transduction pathways triggered by tyrosine kinases. Thus, Sam68 participates in the signaling of T cell receptors, leptin and insulin receptors. In these systems Sam68 is tyrosine phosphorylated and recruited to specific signaling complexes. The participation of Sam68 in signaling suggests that it may function as an adaptor molecule, working as a dock to recruit other signaling molecules. Finally, the connection between this role of Sam68 in protein-protein interaction with RNA binding activity may connect signal transduction of tyrosine kinases with the regulation of RNA metabolism.

Adaptor Proteins, Signal Transducing↗

PubMed2002

The human telomerase RNA gene (hTERC) is regulated during carcinogenesis but is not dependent on DNA methylation.

Telomerase, the ribonucleoprotein complex involved in telomere maintenance, is composed of two main components: hTERT and hTERC. hTERT seems to be the rate-limiting factor for telomerase activity, although hTERC expression was also shown to correlate to a certain extent with telomerase reactivation. To determine whether the absence of hTERC expression could be the consequence of DNA methylation, we quantified hTERC RNA in 60 human samples (19 telomerase-negative normal tissues, nine telomerase-positive and 22 telomerase-negative tumor tissues, eight telomerase-positive and two telomerase-negative cell lines) using a quantitative dot blot on RT-PCR products. Most of the normal tissues did not express hTERC whereas, in telomerase-positive cell lines and in telomerase-positive tumor tissues, a strong up-regulation was observed, suggesting that hTERC transcription is up-regulated during tumorigenesis. The two telomerase-negative cell lines did not express hTERC. In a series of 22 telomerase-negative soft tissue sarcomas (STS), half did not express hTERC at all, or only weakly, whereas a wide range of expression was observed in the other half. As methylation might be involved in hTERC silencing, we examined the methylation pattern in all samples by direct sequencing and methylation-specific single stand conformation analysis after bisulfite modification. hTERC methylation was never observed, neither in normal nor in tumor tissues. Furthermore, there was no correlation between hTERC expression and proliferation, telomere length or hTERT expression in telomerase-negative STS. In contrast, three of eight telomerase-positive cell lines and the two telomerase negative cell lines were found to be hypermethylated, suggesting that the methylation observed may occur during cell line establishment. In conclusion, this study shows that hTERC expression is indeed regulated during carcinogenesis, but this regulation is unlikely to depend on hTERC methylation, cell proliferation rate, telomere length or hTERT expression.

Antimetabolites, Antineoplastic↗

PubMed2000

A pAD1-encoded small RNA molecule, mD, negatively regulates Enterococcus faecalis pheromone response by enhancing transcription termination.

pAD1 is a 60-kb hemolysin-bacteriocin plasmid in Enterococcus faecalis that encodes a conjugative mating response to a peptide sex pheromone, cAD1, secreted by plasmid-free bacteria. The pheromone response is regulated by two proteins: TraE1, which positively regulates all or most conjugative structural genes, and TraA, which negatively regulates traE1. TraA binds to pAD1 DNA at the iad (encoding the inhibitor peptide iAD1) promoter but is released upon binding to imported pheromone. This leads to enhanced transcription through two closely spaced downstream terminators (t1 and t2) into traE1. TraE1 is believed to then upregulate itself from a site located within t2; thus, a small amount of transcription through t1-t2 could lead to overall induction. It is important therefore that the t1-t2 terminators be tightly controlled to keep the response shut down in the absence of pheromone. A small (200-nucleotide) RNA molecule designated mD is encoded just upstream of t1 by a determinant (traD) oriented in the direction opposite to that of transcripts utilizing t1. mD is expressed at high levels in the uninduced state, but it decreases significantly upon induction. Here we present results of genetic studies relating to the activity of t1-t2 and show that mD strongly enhances transcriptional termination at t1. The mD activity is shown to influence transcription well downstream and can affect the determinant for aggregation substance asa1. The phenomenon is specific in that there is no effect of mD on the unrelated pheromone-responding plasmids pPD1 and pCF10.

Bacterial Proteins↗

PubMed1988

[Role of the NS gene in regulating the synthesis of RNA-segments of the influenza A virus].

To find the role of any influenza virus gene in regulation of the RNA-segments replication the transfer of ts-mutants to nonpermissive temperature on the late step of infection has been used (shift-up). The mutants having impaired the NS or NP-genes have been obtained and studied. The transfer of mutants to partially nonpermissive conditions (when the amount of replication is decreased, but it still continues) results in the distinct return to the early mode of replication in ts-mutant with the mutation in NS-gene. This suggests the NS-gene role in replication of viral RNA-segments, in particular, in the switch from the "early" stage of replication to the "late" one. In NP-gene mutant only the decrease in general replication takes place without the shift to "early" replication mode.

Electrophoresis, Polyacrylamide Gel↗

PubMed1997

A conserved RNA-binding protein that regulates sexual fates in the C. elegans hermaphrodite germ line.

The nematode Caenorhabditis elegans has two sexes, males and hermaphrodites. Hermaphrodites Initially produce sperm but switch to producing oocytes. This switch appears to be controlled by the 3' untranslated region of fem-3 messenger RNA. We have now identified a binding factor (FBF) which is a cytoplasmic protein that binds specifically to the regulatory region of fem-3 3'UTR and mediates the sperm/oocyte switch. The RNA-binding domain of FBF consists of a stretch of eight tandem repeats and two short flanking regions. This structural element is conserved in several proteins including Drosophila Pumilio, a regulatory protein that controls pattern formation in the fly by binding to a 3'UTR. We propose that FBF and Pumilio are members of a widespread family of sequence-specific RNA-binding proteins.

Amino Acid Sequence↗

PubMed1991

Cytochrome P450 side-chain cleavage (P450scc) in the hen ovary. I. Regulation of P450scc messenger RNA levels and steroidogenesis in theca cells of developing follicles.

We have recently shown that granulosa cells from hen ovarian follicles, collected at a stage of development 2-3 wk prior to ovulation (e.g. 6-8 mm in diameter) are steroidogenically inactive. Therefore, the hypothesis tested in the present studies was that theca cells from follicles at this stage of development must contain sufficient levels of functional cytochrome P450 side-chain cleavage (P450scc) enzyme to produce the progestin precursor required for the synthesis of androgens and estrogens. Northern blot analysis of total theca RNA collected from 6-8-mm follicles indicated the presence of a single P450scc mRNA transcript of approximately 2 kb whose expression was increased following an 8-h preincubation with 200 ng/ml ovine LH (oLH) or 10 microM forskolin. Western blot analysis of crude mitochondrial protein revealed a band of immunoreactive P450scc protein of approximately 53 kDa that was determined to be capable of converting 25-hydroxycholesterol to pregnenolone in a cell-free system. In the second set of studies, conducted to examine the cellular regulation of steroidogenesis in isolated theca cells of 6-8-mm follicles, theca cells were found to produce measurable basal levels of cAMP, progesterone, androstenedione, and estradiol following a 3-h incubation of 5 x 10(5) cells. Furthermore, significant dose-dependent increases in steroidogenesis were observed in response to oLH (0.2-200 ng/ml), chicken FSH (cFSH; 20-200 ng/ml), cholera toxin (0.002-20 ng/ml), and 8-bromo-cAMP (0.1-3.33 mM). Phorbol 12-myristate 13-acetate (PMA; 10-167 nM) also stimulated dose-dependent increases in basal progesterone, androstenedione, and estradiol production. In addition, while PMA had no effect on oLH (200 ng/ml)-promoted cAMP accumulation, or on oLH (20 ng/ml)- or 8-bromo-cAMP (1 mM)-stimulated progesterone production, it attenuated oLH-induced and 8-bromo-cAMP-induced androstenedione and estradiol accumulation. We conclude that theca cells from 6-8-mm follicles possess mRNA and immunoreactive protein coding for functional P450scc. Furthermore, basal steroidogenesis is increased by both the protein kinase A and protein kinase C pathways, whereas evidence suggests that protein kinase C inhibits LH-induced androstenedione production at a site distal to cAMP and progesterone production, most likely by decreasing C17,20-lyase activity.

Androstenedione↗

PubMed1988

Messenger RNA structure and gene regulation at the translational level in Escherichia coli: the case of threonine:tRNAThr ligase.

Previous work showed that the expression of the Escherichia coli threonine:tRNAThr ligase (EC 6.1.1.3)-encoding gene (thrS) is negatively autoregulated at the translational level and that a region called the operator that is located between 10 and 50 base pairs upstream of the translation initiation codon of the thrS gene is directly involved in that control. The conformation of an in vitro synthesized RNA fragment extending over the thrS regulatory region has been investigated using chemical and enzymatic probes. This study shows that the RNA folds into four well-defined secondary-structure domains, one of them displaying structural similarities to the anticodon arm of tRNAThr. The conformation of three constitutive mutants containing single base changes in the operator region leading to the loss of the regulatory control was also investigated. The replacement of a base in the anticodon-like loop does not induce any conformational change, suggesting that the residue concerned is directly involved in the regulatory process. However, single mutations in or close to the anticodon-like stem result in a partial or complete reorganization of the structure of the operator region. These rearrangements should affect the binding of the ligase to the operator, leading to loss of the regulatory process.

Amino Acyl-tRNA Synthetases↗

PubMed1995

Hyperadrenocorticism and food restriction-induced life extension in the rat: evidence for divergent regulation of pituitary proopiomelanocortin RNA and adrenocorticotropic hormone biosynthesis.

The increased diurnal elevation of plasma corticosterone (B) induced by food restriction (FR) may play a role in the life span extension of FR. We investigated whether FR alters adrenocorticotropic hormone (ACTH) and proopiomelanocortin (POMC) mRNA levels in plasma and anterior pituitary (AP), since these molecules both regulate and can be suppressed by B. Measurements were made in 3-month-old male Fischer 344 rats that had been ad libitum (AL) or FR (60% of AL calories) since 6 weeks of age. Plasma B was 2-fold higher in FR rats in the PM samples, but did not differ in AM samples. By contrast, plasma ACTH did not differ in the PM samples of FR and AL rats and was 20% lower in AM samples (p < .05) of FR rats. AP content of ACTH was 50% lower in FR rats in both AM and PM samples (p < .01). In contrast, AP contents of POMC and mRNA, primary transcript, and processing intermediate were not reduced in FR rats, and PM content of POMC primary transcript was elevated in FR rats (p < .05). The reduced pituitary and plasma ACTH of FR rats may be the consequence of their elevated plasma B levels. This study also suggests that factors other than elevated ACTH account for FR-induced hyperadrenocorticism. These results also indicate that POMC mRNA and ACTH biosyntheses are differentially regulated in FR rats.

Adrenocorticotropic Hormone↗

PubMed2004

Molecular interplay between RNA polymerase and two transcriptional regulators in promoter switch.

Transcription regulation relies in the molecular interplay between the RNA polymerase (RNAP) and regulatory factors. Phage phi29 promoters A2c, A2b and A3 are coordinately regulated by the transcriptional regulator protein p4 and the histone-like protein p6. This study shows that protein p4 binds simultaneously to four sites: sites 1 and 2 located between promoters A2c and A2b and sites 3 and 4 between promoters A2b and A3, placed in such a way that bound p4 is equidistant from promoters A2c and A2b and one helix turn further upstream from promoter A3. The p4 molecules bound to sites 1 and 3 reorganise the binding of protein p6, giving rise to the nucleoprotein complex responsible for the switch from early to late transcription. We identify the positioning of the alphaCTD-RNAP domain at these promoters, and demonstrate that the domains are crucial for promoter A2b recognition and required for full activity of promoter A2c. Since binding of RNAP overlaps with p4 and p6 binding, repression of the early transcription relies on the synergy of the regulators able to antagonize the stable binding of the RNAP through competition for the same target, while activation of late transcription is carried out through the stabilization of the RNAP by the p4/p6 nucleoprotein complex. The control of promoters A2c and A2b by feed-back regulation is discussed.

Bacteriophages↗