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PubMed2002

High pressure effects on cellular expression profile and mRNA stability. A cDNA array analysis.

Hydrostatic pressure has a profound effect on cartilage tissue and chondrocyte metabolism. Depending on the type and magnitude of pressure various responses can occur in the cells. The mechanisms of mechanotransduction at cellular level and the events leading to specific changes in gene expression are still poorly understood. We have previously shown that induction of stress response in immortalized chondrocytes exposed to high static hydrostatic pressure increases the stability of heat shock protein 70 mRNA. In this study, our aim was to examine the effect of high pressure on gene expression profile and to study whether stabilization of mRNA molecules is a general phenomenon under this condition. For this purpose a cDNA array analysis was used to compare mRNA expression profile in pressurized vs. non-pressurized human chondrosarcoma cells (HCS 2/8). mRNA stability was analyzed using actinomycin-treated and nontreated samples collected after pressure treatment. A number of immediate-early genes, and genes regulating cell cycle and growth were up-regulated due to high pressure. Decrease in osteonectin, fibronectin, and collagen types VI and XVI mRNAs was observed. Also bikunin, cdc37 homologue and Tiam1, genes linked with hyaluronan metabolism, were down-regulated. In general, stability of down-regulated mRNA species appeared to increase. However, no increase in mRNA above control level due to stabilization was noticed in the genes available in the array. On the other hand, mRNAs of certain immediate-early genes, like c-jun, jun-B and c-myc, became destabilized under pressure treatment. Increased accumulation of mRNA on account of stabilization under high pressure conditions seems to be a tightly regulated, specific phenomenon.

Cartilage, Articular↗
PubMed1991

Multiple determinants of functional mRNA stability: sequence alterations at either end of the lacZ gene affect the rate of mRNA inactivation.

The Escherichia coli lacZ gene was used as a model system to identify specific sequence elements affecting mRNA stability. Various insertions and substitutions at the ribosome-binding site increased or decreased the rate of mRNA inactivation by up to fourfold. Deletion of a dyad symmetry, which may give rise to a very stable secondary structure in the mRNA immediately downstream of the gene, decreased the functional stability of the lacZ message. The magnitude of the latter effect was strongly dependent on the sequences at the ribosome-binding site, ranging from practically no effect for the most labile transcripts to a threefold decrease in stability for the most stable one. The results suggest that the wild-type lacZ message is inactivated predominantly by attacks near the ribosome-binding site, presumably in part because the putative secondary structure downstream of the gene protects against 3'-exonucleolytic attack. Taken together, the data for all of the modified variants of lacZ were shown to be quantitatively compatible with a general model of mRNA inactivation involving multiple independent target sites.

Base Sequence↗
PubMed1995

Transcription and mRNA stability regulate developmental and hormonal expression of rabbit surfactant protein B gene.

Surfactant protein B (SP-B), a hydrophobic protein of pulmonary surfactant, is essential for the surface tension-reducing properties of surfactant. In the present study, we isolated and characterized cDNAs encoding rabbit SP-B, and used transcription run-on assays and Northern blot analysis to investigate the role of transcriptional and posttranscriptional mechanisms in the developmental and cAMP and dexamethasone induction of SP-B mRNA. We found two forms of SP-B cDNAs that differed by an insertion of 69 nucleotides in the 3' untranslated regions. We found that transcription across the SP-B gene is nonequimolar and the 3' end of the gene has high levels of antisense transcription. SP-B gene transcription and SP-B mRNA levels increased during fetal lung development. However, increased SP-B mRNA levels could not be accounted for primarily on the basis of increased transcription. These results suggested that enhanced SP-B gene transcription and enhanced SP-B mRNA stability mediate developmental induction of SP-B gene. In rabbit fetal lung in vitro, both dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) and dexamethasone increased SP-B mRNA levels. DBcAMP-dependent increase in SP-B mRNA levels resulted from increased SP-B gene transcription, whereas dexamethasone-dependent increase resulted from combined effects on increased SP-B gene transcription and SP-B mRNA stability. In tissues treated with dexamethasone the half-life (t1/2) of SP-B mRNA increased > 2.5-fold (t1/2 control = 9 h; t1/2 dex-treated = 25 h). These data show that both transcription and mRNA stability regulate induction of SP-B gene expression during fetal lung development and by cAMP and dexamethasone in fetal lung in vitro.

Amino Acid Sequence↗
PubMed1992

mRNA stability: in trans-it.

The regulation of mRNA stability is an important step in the control of gene expression. Characterization of the mechanisms involved in the turnover of individual mRNAs has identified a requirement for specific cis-acting sequences and trans-acting factors, as well as an involvement of the translation apparatus. In the past year, significant progress has been made in the identification of trans-acting factors by both biochemical and genetic approaches. This review summarizes that progress and promotes the notion that the ribosome itself should also be considered as a trans-acting component of the mRNA decay machinery.

Animals↗
PubMed2005

Control of gene expression during T cell activation: alternate regulation of mRNA transcription and mRNA stability.

BACKGROUND: Microarray technology has become highly valuable for identifying complex global changes in gene expression patterns. The effective correlation of observed changes in gene expression with shared transcription regulatory elements remains difficult to demonstrate convincingly. One reason for this difficulty may result from the intricate convergence of both transcriptional and mRNA turnover events which, together, directly influence steady-state mRNA levels. RESULTS: In order to investigate the relative contribution of gene transcription and changes in mRNA stability regulation to standard analyses of gene expression, we used two distinct microarray methods which individually measure nuclear gene transcription and changes in polyA mRNA gene expression. Gene expression profiles were obtained from both polyA mRNA (whole-cell) and nuclear run-on (newly transcribed) RNA across a time course of one hour following the activation of human Jurkat T cells with PMA plus ionomycin. Comparative analysis revealed that regulation of mRNA stability may account for as much as 50% of all measurements of changes in polyA mRNA in this system, as inferred by the absence of any corresponding regulation of nuclear gene transcription activity for these groups of genes. Genes which displayed dramatic elevations in both mRNA and nuclear run-on RNA were shown to be inhibited by Actinomycin D (ActD) pre-treatment of cells while large numbers of genes regulated only through altered mRNA turnover (both up and down) were ActD-resistant. Consistent patterns across the time course were observed for both transcribed and stability-regulated genes. CONCLUSION: We propose that regulation of mRNA stability contributes significantly to the observed changes in gene expression in response to external stimuli, as measured by high throughput systems.

Cell Nucleus↗
PubMed2006

The exon 6ABC region of amelogenin mRNA contribute to increased levels of amelogenin mRNA through amelogenin protein-enhanced mRNA stabilization.

We recently demonstrated that the reuptake of full-length amelogenin protein results in increased levels of amelogenin mRNA through enhanced mRNA stabilization (Xu, L., Harada, H., Tamaki, T. Y., Matsumoto, S., Tanaka, J., and Taniguchi, A. (2006) J. Biol. Chem. 281, 2257-2262). Here, we examined the molecular mechanism of enhanced amelogenin mRNA stabilization. To identify the cis-regulatory region within amelogenin mRNA, we tested various reporter systems using a deletion series of reporter plasmids. A deletion at exon 6ABC of amelogenin mRNA resulted in a 2.5-fold increase in the amelogenin mRNA expression level when compared with that of full-length mRNA, indicating that a cis-element exists in exon 6ABC of amelogenin mRNA. Furthermore, Northwestern analysis demonstrated that amelogenin protein binds directly to its mRNA in vitro, suggesting that amelogenin protein acts as a trans-acting protein that specifically binds to this cis-element. Moreover, recombinant mouse amelogenin protein extended the half-life of full-length amelogenin mRNA but did not significantly alter the half-life of exon 6ABC-deletion mutant mRNA. The splice products produced by deletion of exon 6ABC are known as leucine-rich amelogenin peptides and have signaling effects on cells. Our findings also suggest that the regulation of full-length amelogenin protein expression differs from the regulation of leucine-rich amelogenin peptide expression.

Amelogenin↗
PubMed2007

Relationship between mRNA stability and length: an old question with a new twist.

The half-life of individual mRNA plays a central role in controlling the level of gene expression. However, the determinants of mRNA stability have not yet been well defined. Most previous studies suggest that mRNA length does not affect its stability. Here, we show significant negative correlations between mRNA length and stability in human and Escherichia coli, but not in Saccharomyces cerevisiae or Bacillus subtilis. This finding suggests the possibility that endonucleolytic attacks by RNA endonuclease and/or mechanical damage may strongly influence mRNA stability in both prokaryotes and eukaryotes.

Bacillus subtilis↗
PubMed1998

mRNA stability and plasmid copy number effects on gene expression from an inducible promoter system.

The effects of mRNA stability and plasmid copy number on gene expression in Escherichia coli were evaluated by constructing multicopy (pMB1-based) and low-copy (F-based) plasmids containing an arabinose-inducible promoter system, the lacZ reporter gene, and mRNA-stabilizing 5' hairpin structures. Product formation and cell growth were evaluated under a number of inducer concentrations. The introduction of a 5' hairpin into the untranslated region of the mRNA resulted in significantly higher gene expression from the multicopy plasmids at low inducer concentrations and increased gene expression from the low-copy plasmids across all inducer concentrations investigated. With high inducer concentrations, expression from high-copy plasmids significantly slowed cell growth, whereas expression from the low-copy plasmids had little effect on growth rate. At inducer concentrations between 1 x 10(-4) and 4 x 10(-4)%, the productivity of low-copy plasmids containing the 5'-hairpin was equal to or greater than that from multicopy plasmids. Together, these two gene expression strategies may find important use in metabolic engineering and heterologous gene expression.

Arabinose↗
PubMed1989

3' noncoding region of phosphoenolpyruvate carboxykinase mRNA contains a glucocorticoid-responsive mRNA-stabilizing element.

The stabilization of phosphoenolpyruvate carboxykinase mRNA by glucocorticoids appears to result from the interaction of an induced factor with an RNA element located in the 3' noncoding sequence of the mRNA. This element can confer glucocorticoid-dependent stabilization upon a heterologous mRNA, and thus strategies developed to investigate the control of mRNA transcription can now be applied to the analysis of hormone-regulated mRNA stabilization.

Animals↗
PubMed1998

Increased nerve growth factor mRNA stability may underlie elevated nerve growth factor secretion from hypertensive vascular smooth muscle cells.

Altered nerve growth factor (NGF) regulation has been linked to the pathophysiology of hypertension. Vascular smooth muscle cells from an inbred hypertensive, but normoactive rat strain (WKHT) secreted NGF at a greater rate than from a hyperactive, normotensive strain (WKHA). Exposure to phorbol ester increased NGF secretion rates from WKHT by 400-800% but not from WKHA vascular muscle. NGF secretion rates from both WKHT and WKHA vascular cells were elevated by co-application of platelet-derived growth factor (PDGF) and transforming growth factor-beta1 (TGF-beta1) by 300-1000%. This response was partially attenuated by actinomycin D, an inhibitor of RNA transcription. These results suggest that regulation of NGF production does not occur solely at the level of transcription and post-transcriptional mechanisms operate. Analysis of NGF mRNA stability in the two strains following PDGF and TGF-beta1 treatment showed that NGF mRNA in WKHT had a half-life of 126.2+/-11.68 min while in WKHA vascular smooth muscle cells, the half-life was 47. 33+/-11.98 min. In addition to increased NGF mRNA stability in WKHT vascular muscle, these cells have an increased translational efficiency of NGF protein; elevated synthesis of NGF protein per unit NGF mRNA. Differences in signaling pathways may result in increased NGF mRNA stability and translational efficiency that may account for the elevated NGF protein in WKHT vascular smooth muscle cells.

Animals↗
PubMed2002

Nuclear export of NF90 is required for interleukin-2 mRNA stabilization.

In response to T cell activation signals, the half-life of interleukin-2 (IL-2) mRNA is greatly extended. The cis elements mediating IL-2 mRNA stabilization are located in its 5' and 3' untranslated regions (UTR). The 3'UTR also contains AU-rich elements (AREs) that mediate rapid IL-2 mRNA degradation in the cytoplasm of nonstimulated T cells. NF90, a previously described RNA binding protein, binds to a subregion of the 3'UTR that contains several AREs and slows down the degradation of IL-2 mRNA. In nonstimulated cells, NF90 is mostly nuclear, but T cell activation results in its accumulation in the cytoplasm. The nuclear export of NF90 is required for IL-2 mRNA stabilization.

3' Untranslated Regions↗
PubMed1998

The 3' untranslated region of a rice alpha-amylase gene functions as a sugar-dependent mRNA stability determinant.

In plants, sugar feedback regulation provides a mechanism for control of carbohydrate allocation and utilization among tissues and organs. The sugar repression of alpha-amylase gene expression in rice provides an ideal model for studying the mechanism of sugar feedback regulation. We have shown previously that sugar repression of alpha-amylase gene expression in rice suspension cells involves control of both transcription rate and mRNA stability. The alpha-amylase mRNA is significantly more stable in sucrose-starved cells than in sucrose-provided cells. To elucidate the mechanism of sugar-dependent mRNA turnover, we have examined the effect of alphaAmy3 3' untranslated region (UTR) on mRNA stability by functional analyses in transformed rice suspension cells. We found that the entire alphaAmy3 3' UTR and two of its subdomains can independently mediate sugar-dependent repression of reporter mRNA accumulation. Analysis of reporter mRNA half-lives demonstrated that the entire alphaAmy3 3' UTR and the two subdomains each functioned as a sugar-dependent destabilizing determinant in the turnover of mRNA. Nuclear run-on transcription analysis further confirmed that the alphaAmy3 3' UTR and the two subdomains did not affect the transcription rate of promoter. The identification of sequence elements in the alpha-amylase mRNA that dictate the differential stability has very important implications for the study of sugar-dependent mRNA decay mechanisms.

Base Sequence↗
PubMed2002

MRNA stability and the control of gene expression: implications for human disease.

Regulation of gene expression is essential for the homeostasis of an organism, playing a pivotal role in cellular proliferation, differentiation, and response to specific stimuli. Multiple studies over the last two decades have demonstrated that the modulation of mRNA stability plays an important role in regulating gene expression. The stability of a given mRNA transcript is determined by the presence of sequences within an mRNA known as cis-elements, which can be bound by trans-acting RNA-binding proteins to inhibit or enhance mRNA decay. These cis-trans interactions are subject to a control by a wide variety of factors including hypoxia, hormones, and cytokines. In this review, we describe mRNA biosynthesis and degradation, and detail the cis-elements and RNA-binding proteins known to affect mRNA turnover. We present recent examples in which dysregulation of mRNA stability has been associated with human diseases including cancer, inflammatory disease, and Alzheimer's disease.

Gene Expression Regulation↗
PubMed1998

[Post-transcriptional regulation of gene expression in eukaryotes: effect of stressors on mRNA stability in vitro].

The effect of field drought on gene expression in developing Zea mays L. grain and the influence of the imbalance of essential amino acids on the expression of genes in white-rat liver at the mRNA stability level were studied. A special ommp system, which included incubation (65 degrees C, 5 min) of an aqueous preparation of highly purified, high molecular-weight RNA isolated in the presence of Mg2+, was used for the analysis of mRNAs relative stability in eukaryotes. Drought changed the relative stability of seven specific mRNA in the maize developing grain: there occurred a considerable stabilization of the eEF-1 alpha mRNA and, conversely, a destabilization of the 19-kDa zein mRNA. The imbalance for lysine and tryptophan reduced the stability of the total polyadenylated mRNA and the eEF-1 alpha mRNA of rat liver. The mRNA stability positively correlated with animal growth. Thus, using the ommp system, the effect of stressful factors on the stability of specific mRNA in eukaryotes--depending on mRNA species, stressful factors, and the tissue--was shown.

Animals↗
PubMed1999

TGF-beta(1), regulation of alzheimer amyloid precursor protein mRNA expression in a normal human astrocyte cell line: mRNA stabilization.

The transforming growth factor, TGF-beta(1), has been found to be increased in the central nervous system of Alzheimer's disease (AD) patients, elevates amyloid precursor protein (APP) mRNA levels in rat primary astrocytes, and may initiate or promote the deposition of amyloid-beta (Abeta) peptide in AD. Excess APP production in AD, which potentially leads to amyloidogenesis, is in part due to over expression of APP mRNA. The production of APP in a normal human cell line in contrast to transformed or animal cells provides a meaningful model to study the regulation of APP gene expression by cytokines that promotes amyloidogenesis. Here, we report that TGF-beta(1) treatment of human astrocytes markedly elevated APP mRNA levels, and also increased the half-life of APP message by at least five-fold. Under this condition, as detected by mobility shift and UV cross-linking analysis, a novel 68 kDa RNA-protein complex was formed, involving an 81 nucleotide (nt) fragment within the 3'-untranslated region (UTR), but not the 5'-UTR and coding region of APP mRNA. Insertion of the 3'-UTR onto the chloramphenicol acetyl transferase (CAT) mRNA conferred TGF-beta(1) mediated mRNA stability in transfected human astrocytes. On the other hand, the same insert carrying a deletion of the APP mRNA cis-element fragment had no effect on CAT mRNA stability. A model of APP mRNA regulation is presented in which TGF-beta(1) induced stabilization of APP message involves the binding activity of a 68 kDa RNA-protein complex within the 3'-UTR, which is likely linked to a reduction in the rate of APP mRNA decay.

3' Untranslated Regions↗
PubMed1992

Tumor necrosis factor alpha-induced glucose transporter (GLUT-1) mRNA stabilization in 3T3-L1 preadipocytes. Regulation by the adenosine-uridine binding factor.

Tumor necrosis factor alpha (TNF alpha), 12-O-tetradecanoylphorbol-13-acetate and cAMP stimulate hexose transport in quiescent 3T3-L1 preadipocytes by stabilizing the relatively labile mRNA coding for the basal glucose transporter, GLUT-1. The 3'-UTR of GLUT-1 mRNA contains a single copy of the destabilizing AUUUA motif in the context of an AU-rich region. The adenosine-uridine binding factor (AUBF) is a cytosolic protein which interacts with similar AU-rich regions in a variety of labile cytokine and oncogene mRNAs. Here, we demonstrate that AUBF complexes in vitro with GLUT-1 mRNA through the AU-rich portion of the 3'-UTR. AUBF activity is very low in quiescent preadipocytes, but can be up-regulated by agonists such as TPA, TNF alpha, cAMP, and okadaic acid, all of which stabilize GLUT-1 mRNA. The time courses of TNF alpha- and TPA-mediated AUBF up-regulation and GLUT-1 mRNA stabilization are coincident, suggesting a cause and effect relationship.

3T3 Cells↗
PubMed2004

Activity-dependent transcriptional activation and mRNA stabilization for cumulative expression of pituitary adenylate cyclase-activating polypeptide mRNA controlled by calcium and cAMP signals in neurons.

Although it has been established that an activity-dependent gene transcription is induced by the calcium (Ca(2+)) signals in neurons, it is unclear how the specific mRNA moieties are transiently accumulated in response to synaptic transmission which evokes multiple intracellular signals including Ca(2+) and cAMP ones. The expression of pituitary adenylate cyclase activating polypeptide (PACAP), a neuropeptide, is controlled by Ca(2+) signals evoked via membrane depolarization in neurons, and, in cultured rat cortical neuronal cells, we found that the Ca(2+) signal-mediated activation of the PACAP gene promoter was critically controlled by a single cAMP-response element (CRE) located at around -200, to which the CRE-binding protein predominantly bound. The Ca(2+) signal-induced expression of PACAP mRNA was enhanced by forskolin, which evokes cAMP signals. In support, the PACAP gene promoter was synergistically enhanced by Ca(2+) and cAMP signals through the CRE, accompanying a prolonged activation of extracellular signal-related protein kinase 1/2 and CRE-binding protein. On the other hand, sole administration of forskolin markedly reduced the cellular content of PACAP mRNA, which was restored by the addition of Ca(2+) signals. We found that the stability of PACAP mRNA was increased in response to Ca(2+) signals but not that of activity-regulated cytoskeleton-associated protein (Arc) mRNA, indicating an activity-dependent stabilization of specific mRNA species in neurons, which can antagonize the regulation mediated by cAMP signals. Thus, the transcriptional activation and mRNA stabilization are coordinately regulated by Ca(2+) and cAMP signals for the cumulative expression of PACAP mRNA in neurons.

Animals↗
PubMed2006

Tristetraprolin regulates Cyclin D1 and c-Myc mRNA stability in response to rapamycin in an Akt-dependent manner via p38 MAPK signaling.

The differential expression of the critical cell cycle control proteins cyclin D1 and c-myc has been shown to result in Akt-dependent hypersensitivity of tumor cells to mTOR inhibitors. We have previously demonstrated that the differential utilization of internal ribosome entry sites within the mRNAs of these transcripts allows maintenance of protein synthesis in the face of rapamycin (rapa) exposure in an Akt-dependent manner. Here, we demonstrate that in addition to this mechanism, cyclin D1 and c-myc mRNA stability is also coordinately regulated following rapa treatment depending on Akt activity status. We identify A/U-rich response elements within the 3' untranslated regions (UTRs) of these transcripts, which confer the observed differential stabilities and show that the RNA-binding protein, tristetraprolin (TTP), interacts with these elements. We also present evidence that TTP accumulates in response to rapa exposure, binds to the cis-acting elements within the cyclin D1 and c-myc 3' UTRs and is differentially serine phosphorylated in an Akt-dependent manner. Furthermore, the differential phosphorylation status of TTP results in its sequestration by 14-3-3 proteins in quiescent Akt-containing cells. Finally, siRNA-mediated knockdown of TTP expression or inhibiting a known regulator of TTP phosphorylation, p38 MAP kinase, abolishes the effects on cyclin D1 and c-myc mRNA stability. We assume that the differential control of cyclin D1 and c-myc mRNA stability and translational efficiency constitutes a coordinate response to rapa contributing to the maintenance of expression of these determinants in rapa-resistant quiescent Akt-containing cells following exposure.

14-3-3 Proteins↗