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At least 343 records · Page 19Linked to original sources
PubMed1987

Biological consequences of segmental alterations in mRNA stability: effects of deletion of the intercistronic hairpin loop region of the Rhodobacter capsulatus puf operon.

It has been proposed that intercistronic stem and loop structures located in the puf operon of the photosynthetic bacterium Rhodobacter capsulatus account for segmental differences in transcript stability and consequently, the differential expression of the B870 and reaction center (RC) proteins encoded by puf. We report here that deletion of these structures leads to a failure to detect as discrete fragments the B870-encoding 0.49 kb and 0.50 kb mRNA segments located upstream from the site of the hairpins. The absence of these stable transcript fragments is associated with altered stoichiometry of the B870 and RC pigment-protein complexes in the bacterial intracytoplasmic membrane and a decreased rate of cell growth under photosynthetic conditions. These results support the view that the hairpin loop structures of the puf intercistronic region function in vivo to impede exoribonucleolytic degradation of upstream mRNA and establish that segmental variations in mRNA stability have a biologically important role in regulating the expression of puf operon genes.

Base Sequence↗
PubMed2004

Radiation-induced up-regulation of Mmp2 involves increased mRNA stability, redox modulation, and MAPK activation.

We have previously observed time- and dose-dependent increases in matrix metalloproteinase 2 (Mmp2) protein levels in rat tubule epithelial cells (NRK52E) after irradiation. However, the mechanism(s) involved remains unclear. In the present study, irradiating NRK52E cells with 0-20 Gy gamma rays was associated with time- and dose-dependent increases in Mmp2 mRNA. Studies using the transcription inhibitor actinomycin D (ActD) added 24 h after irradiation revealed the t(1/2) of Mmp2 mRNA to be approximately 8 h in control cells. In contrast, the increase in Mmp2 mRNA levels in irradiated cells was essentially unchanged after incubation with ActD for up to 12 h. Incubating cells with the antioxidants N-acetylcysteine or ebselen or the MEK pathway inhibitors PD98059 and U0126 prior to irradiation abolished the radiation-induced up-regulation of Mmp2. Irradiating NRK52E cells led to reactive oxygen species-mediated Erk1/2 activation; preincubation with NAC prevented the radiation-induced increase in phosphorylated Erk1/2. Transfecting cells with a dominant-negative ERK mutant completely inhibited radiation-induced Erk phosphorylation and abolished the radiation-induced up-regulation of Mmp2 protein. Thus the radiation-induced up-regulation of Mmp2 mRNA is due in part to increased mRNA stability and is mediated by redox; the ERK MAPK signaling pathway may be involved.

Animals↗
PubMed2006

Heterogeneous nuclear ribonucleoprotein-A2/B1 modulate collagen prolyl 4-hydroxylase, alpha (I) mRNA stability.

Collagen prolyl 4-hydroxylase (C-P4H) alpha-subunit is of regulatory importance in the assembling of C-P4H tetramers, which are necessary for the hydroxylation of procollagen chains. Change in collagen expression by hypoxia or iron diminishment is a significant issue in extracellular matrix remodeling. It was proposed that C-P4H-alpha (I) is regulated at the posttrancriptional level under these conditions. Here we report that the induction of C-P4H-alpha (I) in human fibrosarcoma cells HT1080 by the iron chelator 2,2-dipyridyl is predominantly caused by an enhancement of mRNA stability. This effect is mediated by an increased synthesis and binding of heterogeneous nuclear ribonucleoprotein (hnRNP)-A2/B1, which interacts with a (U)(16) element located in the 3'-untranslated region of C-P4H-alpha (I) mRNA. Luciferase reporter gene assays depending on C-P4H-alpha (I) 3'-untranslated region and co-transfection with hnRNP-A2/B1 provide evidence that the (U)(16) element is necessary and sufficient for posttranscriptional control of C-P4H-alpha (I) synthesis under the analyzed conditions. Further indication for the significance of hnRNP-A2/B1 in C-P4H-alpha (I) induction was obtained by micro array experiments. In a data set representing 686 independent physiological conditions, we found a significant positive correlation between hnRNP-A2/B1 and C-P4H-alpha (I) mRNAs.

2,2'-Dipyridyl↗
PubMed2002

Glucose-inducible expression of rrg1+ in Schizosaccharomyces pombe: post-transcriptional regulation of mRNA stability mediated by the downstream region of the poly(A) site.

rrg1+(rapid response to glucose) has been isolated previously as a UV-inducible gene in Schizosaccharomyces pombe, designated as uvi22+. However, it was revealed that the transcript level of this gene was regulated by glucose, not by DNA-damaging agents. Glucose depletion led to a rapid decrease in the level of rrg1+ mRNA, by approximately 50% within 30 min. This effect was readily reversed upon re-introduction of glucose within 1 h. High concentrations (4 and 8%) of glucose showed similar effects on increasing the rrg1+ mRNA level compared with 2% glucose, while a low concentration (0.1%) was not effective in raising the rrg1+ mRNA level. In addition, sucrose and fructose could increase rrg1+ mRNA level. Interestingly, the rapid decline in mRNA level seen upon glucose deprivation resulted from precipitous reduction of mRNA half-life. Serial and internal deletions within the 3'-flanking region of rrg1+ revealed that a 210-nt region downstream of the distal poly(A) site was critical for glucose-regulated expression. Moreover, this downstream region participated in 3'-end formation of mRNA. Taken together, this is the first report on glucose-inducible expression regulated post-transcriptionally by control of mRNA stability in S.pombe.

3' Flanking Region↗
PubMed1998

rbcL Transcript levels in tobacco plastids are independent of light: reduced dark transcription rate is compensated by increased mRNA stability.

The plastid rbcL gene, encoding the large subunit of ribulose-1, 5-bisphosphate carboxylase, in higher plants is transcribed from a sigma70 promoter by the eubacterial-type RNA polymerase. To identify regulatory elements outside of the rbcL -10/-35 promoter core, we constructed transplastomic tobacco plants with uidA reporter genes expressed from rbcL promoter derivatives. Promoter activity was characterized by measuring steady state levels of uidA mRNA on RNA gel blots and by measuring promoter strength in run-on transcription assays. We report here that the rbcL core promoter is sufficient to obtain wild-type rates of transcription. Furthermore, the rates of transcription were up to 10-fold higher in light-grown leaves than in dark-adapted plants. Although the rates of transcription were lower in the dark, rbcL mRNA accumulated to similar levels in light-grown and dark-adapted leaves. Accumulation of uidA mRNA from most rbcL promoter deletion derivatives directly reflected the relative rates of transcription: high in the light-grown and low in the dark-adapted leaves. However, uidA mRNA accumulated to high levels in a light-independent fashion as long as a segment encoding a stem-loop structure in the 5' untranslated region was included in the promoter construct. This finding indicates that lower rates of rbcL transcription in the dark are compensated by increased mRNA stability.

Base Sequence↗
PubMed2002

Activation of p38 alpha MAPK enhances collagenase-1 (matrix metalloproteinase (MMP)-1) and stromelysin-1 (MMP-3) expression by mRNA stabilization.

Here, we have examined the role of distinct MAPK pathways in the regulation of collagenase-1 (matrix metalloproteinase (MMP)-1) and stromelysin-1 (MMP-3) expression by human skin fibroblasts. Tumor necrosis factor-alpha rapidly and transiently activated ERK1/2 and JNK in fibroblasts, whereas the activation of p38 MAPK was more persistent. Inhibition of p38 activity by SB203580 markedly (by 80-90%) inhibited induction of MMP-1 and MMP-3 expression by tumor necrosis factor-alpha, whereas blocking the activation of ERK1/2 by PD98059 had no effect. Activation of endogenous ERK1/2 by adenovirus-mediated transfer of constitutively active MEK1 resulted in potent induction of MMP-1 and MMP-3 expression. Activation of endogenous or adenovirally expressed p38 alpha by adenovirally delivered constitutively active MKK3b and MKK6b also enhanced MMP-1 and MMP-3 expression and augmented the up-regulatory effect of ERK1/2 activation on the expression of these MMPs. Activation of ERK1/2 resulted in induction of c-jun, junB, and c-fos expression, whereas activation of p38 alone had no effect. In contrast, activation of p38 alpha resulted in marked stabilization of MMP-1 and MMP-3 mRNAs. These results identify two distinct and complementary signaling mechanisms mediating induction of MMP-1 and MMP-3 expression in dermal fibroblasts: AP-1-dependent transcriptional activation via the ERK1/2 pathway and AP-1-independent enhancement via p38 alpha MAPK by mRNA stabilization. It is conceivable that both modes of action play an important role in controlling the proteolytic phenotype of fibroblasts, e.g. in wound repair and tumor invasion.

Cells, Cultured↗
PubMed1995

Okadaic acid increases nerve growth factor secretion, mRNA stability, and gene transcription in primary cultures of cortical astrocytes.

Neonatal rat cortical astrocytes in primary culture synthesize and secrete nerve growth factor (NGF) in response to cytokines, growth factors, and activators of protein kinases. To further implicate a protein phosphorylation mechanism in the regulation of NGF expression, astrocytes were treated with okadaic acid and calyculin A, inhibitors of phosphoprotein phosphatases 1 and 2A. Okadaic acid dramatically increased both NGF mRNA content (50-fold) and NGF secretion (100-fold) in astrocytes, while calyculin A, which has a spectrum of phosphatase inhibitory activity different from okadaic acid, failed to augment NGF expression. The increased mRNA accumulation was due mainly to an increase (4-fold) in the half-life of the NGF mRNA following 9 or 24 h of treatment. Nuclear run-on assays indicated that okadaic acid also activated NGF gene transcription, which was preceded by an induction of c-fos and c-jun gene transcription. The induction of NGF expression by okadaic acid appeared independent from protein kinase C activity because down-regulating protein kinase C activity failed to decrease the okadaic acid stimulation. In contrast, interleukin-1 beta acted synergistically with okadaic acid to stimulate NGF secretion. The results indicate that okadaic acid profoundly stimulates NGF expression in astrocytes mainly by enhancing NGF mRNA stability and suggest important roles for phosphoprotein phosphatases in regulating NGF production.

Animals↗
PubMed2000

HuR regulates cyclin A and cyclin B1 mRNA stability during cell proliferation.

Colorectal carcinoma RKO cells expressing reduced levels of the RNA-binding protein HuR (ASHuR) displayed markedly reduced growth. In synchronous RKO populations, HuR was almost exclusively nuclear during early G(1), increasing in the cytoplasm during late G(1), S and G(2). The expression and half-life of mRNAs encoding cyclins A and B1 similarly increased during S and G(2), then declined, indicating that mRNA stabilization contributed to their cell cycle-regulated expression. In gel-shift assays using radiolabeled cyclin RNA transcripts and RKO protein extracts, only those transcripts corresponding to the 3'-untranslated regions of cyclins A and B1 formed RNA-protein complexes in a cell cycle-dependent fashion. HuR directly bound mRNAs encoding cyclins A and B1, as anti-HuR antibodies supershifted such RNA-protein complexes. Importantly, the expression and half-life of mRNAs encoding cyclins A and B1 were reduced in ASHuR RKO cells. Our results indicate that HuR may play a critical role in cell proliferation, at least in part by mediating cell cycle-dependent stabilization of mRNAs encoding cyclins A and B1.

Antigens, Surface↗
PubMed2004

AU-rich elements in the mRNA 3'-untranslated region of the rat receptor for advanced glycation end products and their relevance to mRNA stability.

Several putative polyadenylation sequences and an adenylate plus timidylate rich element (ARE) are present at the 3' end of the rat advanced glycation end products receptor (RAGE) gene. Two transcripts are generated by the use of alternative polyadenylation sequences, one containing the ARE sequence in its 3'-untranslated region (3'-UTR). Transfections of CHO-k1 or NRK cells with constructs expressing the 3'-UTRs of the transcripts fused to a green fluorescence protein mRNA show that the ARE sequence has a negative effect on protein expression correlating with a decrease in the amount of mRNA, as shown in CHO-k1 transfected cells. When transfected cells were incubated in the presence of Actinomycin D the amount of fluorescence decreased in cells transfected with the ARE sequence, indicating that this sequence induces lower mRNA stability. Thus, alternative polyadenylation signals and an ARE sequence provide a novel mechanism for the regulation of the rat RAGE gene expression.

3' Untranslated Regions↗
PubMed2000

Amphotericin B severely affects expression and activity of the endothelial constitutive nitric oxide synthase involving altered mRNA stability.

The therapeutic use of the antifungal drug amphotericin B (AmB) is limited due to severe side effects like glomerular vasoconstriction and risk of renal failure during AmB administration. As nitric oxide (NO) has substantial functions in renal autoregulation, we have determined the effects of AmB on endothelial constitutive NO synthase (ecNOS) expression and activity in human and rat endothelial cell cultures. AmB used at concentrations of 0.6 to 1.25 microg ml(-1) led to increases in ecNOS mRNA and protein expression as well as NO production. This was the result of an increased ecNOS mRNA half-life. In contrast, incubation of cells with higher albeit subtoxic concentrations of AmB (2.5 - 5.0 microg ml(-1)) resulted in a decrease or respectively in completely abolished ecNOS mRNA and protein expression with a strongly reduced or inhibited ecNOS activity, due to a decrease of ecNOS mRNA half-life. None of the AmB concentrations affected promoter activity as found with a reporter gene construct stably transfected into ECV304 cells. Thus, our experiments show a concentration-dependent biphasic effect of AmB on expression and activity of ecNOS, an effect best explained by AmB influencing ecNOS mRNA stability. In view of the known renal accumulation of this drug the results reported here could help to elucidate its renal toxicity.

Amphotericin B↗
PubMed2006

The peptidyl-prolyl isomerase Pin1 regulates granulocyte-macrophage colony-stimulating factor mRNA stability in T lymphocytes.

Cytokine production is associated with both the normal and pathologic inflammatory response to injury. Previous studies have shown that the immunosuppressants cyclosporin A or FK506, which interact with the peptidyl-propyl isomerases cyclophilin A and FK506-binding protein (FKBP12), respectively, block cytokine expression. A third member of the peptidyl-propyl isomerase family, Pin1 is expressed by immune and other cells. Pin1 has been implicated in cell cycle progression, is overexpressed in human tumors, and may rescue neurons from tau-associated degeneration. However, the role of Pin1 in the immune system remains largely unknown. In this study, we analyze the role of Pin1 in GM-CSF expression by human PBMC and CD4+ lymphocytes. We show that Pin1 isomerase activity is necessary for activation-dependent, GM-CSF mRNA stabilization, accumulation, and protein secretion, but not non-AU-rich elements containing cytokine mRNAs, including TGF-beta and IL-4. Mechanistically, Pin1 mediated the association of the AU-rich element-binding protein, AUF1, with GM-CSF mRNA, which determined the rate of decay by the exosome.

CD4-Positive T-Lymphocytes↗
PubMed1989

Cloning of the altered mRNA stability (ams) gene of Escherichia coli K-12.

A temperature-sensitive mutation in the ams gene of Escherichia coli causes an increase in the chemical half-life of pulse-labeled RNA at the nonpermissive temperature. Using lambda clones containing DNA fragments from the 23- to 24-min region on the E. coli chromosome, we have isolated a 5.8-kilobase DNA fragment which, when present in a low-copy-number plasmid, complements the conditional lethality and increased mRNA stability associated with the ams-1 mutation. The approximate initiation site and the direction of transcription of the ams gene were determined from the size of truncated polypeptides produced by Tn1000 insertions and Bal 31 deletions. Overexpression of the ams locus by using a T7 RNA polymerase-promoter system permitted the identification of an ams-encoded polypeptide of 110 kilodaltons.

Blotting, Southern↗
PubMed2005

NF-kappa B-mediated MyoD decay during muscle wasting requires nitric oxide synthase mRNA stabilization, HuR protein, and nitric oxide release.

Muscle wasting (cachexia) is a consequence of chronic diseases, such as cancer, and is associated with degradation of muscle proteins such as MyoD. The cytokines tumor necrosis factor alpha and gamma interferon induce muscle degeneration by activating the transcription factor NF-kappaB and its target genes. Here, we show that a downstream target of NF-kappaB is the nitric oxide (NO) synthase gene (iNos) and suggest that NO production stimulates MyoD mRNA loss. In fact, although cytokine treatment of iNos(-/-) mice activated NF-kappaB, it did not trigger MyoD mRNA degeneration, demonstrating that NF-kappaB-mediated muscle wasting requires an active iNOS-NO pathway. The induced expression of iNOS by cytokines relies on both transcriptional activation via NF-kappaB and increased mRNA stability via the RNA-binding protein HuR. Moreover, we show that HuR regulates iNOS expression in an AMP-activated protein kinase (AMPK)-dependent manner. Furthermore, AMPK activation results in HuR nuclear sequestration, inhibition of iNOS synthesis, and reduction in cytokine-induced MyoD loss. These results define iNOS and HuR as critical players in cytokine-induced cachexia, establishing them as potential therapeutic targets.

Animals↗
PubMed1998

Role of mRNA stability in the different patterns of cytokine production by CD4+ cells from young and old mice.

CD4+ cells from young (3 months) and old (19 months) mice were stimulated by plate-bound anti-CD3 monoclonal antibody (mAb) alone or also by soluble anti-CD28 mAb. Supernatants were analysed by enzyme-linked immunosorbent assay (ELISA) to determine cytokine concentrations. Total RNA was extracted from cells, reverse transcribed and the cDNA amplified by polymerase chain reaction (PCR) to evaluate the amount of specific mRNA. The results indicate that anti-CD3 alone is not sufficient to induce interleukin-2 (IL-2) production in CD4+ cells from both young and old mice. However, anti-CD28, together with anti-CD3 mAb, induces a much higher production of IL-2 in CD4+ cells from young as compared with old mice. Conversely, interferon-gamma (IFN-gamma) production is also induced by anti-CD3 alone and is higher in CD4+ cells from old as compared with young mice. Upon addition of anti-CD28 mAb, IFN-gamma production increases in both groups, but it remains much higher in old than in young mice. Also the production of IL-4 and IL-10 is induced by anti-CD3 mAb but it is increased by the addition of anti-CD28 mAb. CD4+ cells from old mice produce more IL-4 and IL-10 as compared with cells from young mice. The amounts of cytokine specific mRNA in CD4+ cells from young and old mice parallel the cytokine levels in culture supernatants. Results on the mRNA turnover indicate that when CD4+ cells are stimulated by anti-CD3 or costimulated also by anti-CD28 mAb, the IFN-gamma, IL-4 and IL-10 specific mRNAs are more stable in old than in young mice, suggesting that mRNA stability has a relevant role in the different patterns of cytokine production.

Aging↗
PubMed1988

mRNA stability plays a major role in regulating the temperature-specific expression of a Tetrahymena thermophila surface protein.

Synthesis of the serotype H3 (SerH3) surface antigen is temperature dependent and responds within 1 h to a change in incubation conditions (G.A. Bannon, R. Perkins-Dameron, and A. Allen-Nash, Mol. Cell. Biol. 6:3240-3245, 1986). Recently, a Tetrahymena thermophila cDNA clone (pC6; D.W. Martindale and P.J. Bruns, Mol. Cell. Biol. 3:1857-1865, 1983) has been shown to be homologous to a portion of the SerH3 mRNA (F.P. Doerder and R.L. Hallberg, personal communication), and it was shown that the cellular levels of this RNA rapidly decreased when cells were shifted from 30 to 41 degrees C (R.L. Hallberg, K.W. Kraus, and R.C. Findly, Mol. Cell. Biol. 4:2170-2179, 1984). These observations indicate that synthesis of the SerH3 protein is highly regulated in response to temperature and led us to initiate studies to determine the mechanism(s) by which SerH3 gene expression is controlled. Using pC6 as a hybridization probe for the SerH3 mRNA, we have determined that (i) the level of SerH3 protein synthesis is directly correlated with the amount of SerH3 message available for translation; (ii) there is, at most, a twofold difference between the relative transcription rates of SerH3 genes at 30 and 40 degrees C; (iii) the SerH3 mRNA half-life in cells incubated at 30 degrees C is greater than 1 h, whereas the half-life in cells incubated at 40 degrees C is only approximately 3 min. These results demonstrate that Tetrahymena SerH3 surface protein expression is regulated by mRNA abundance. Furthermore, the major mechanism controlling mRNA abundance is a dramatic temperature-dependent change in SerH3 mRNA stability.

Animals↗
PubMed2003

TGFbeta inhibits LPS-induced chemokine mRNA stabilization.

The mechanisms involved in anti-inflammatory action of transforming growth factor beta (TGFbeta) have been examined by evaluating its effect on chemokine gene expression in mouse macrophages. Lipopolysaccharide (LPS)-stimulated expression of the CXC chemokines KC and MIP-2 was selectively reduced by TGFbeta in a time- and protein synthesis-dependent process. While TGFbeta had a modest effect on transcription of the KC and MIP-2 mRNAs as measured by nuclear run-on, it had no effect on LPS-stimulated luciferase expression driven by the KC promoter nor on the activation of nuclear factor kappaB (NFkappaB) DNA-binding activity and transactivation function. Interestingly, KC mRNA levels were markedly reduced by TGFbeta treatment in cells transfected with KC genomic or cDNA constructs driven from either the KC or cytomegalovirus (CMV) promoters, demonstrating the importance of sequences within the mature mRNA and suggesting that suppression may involve a posttranscriptional mechanism. In support of this possibility, LPS stimulation prolonged the half-life of KC mRNA and this stabilization response was blocked in cells treated with TGFbeta. Examination of KC mRNA expressed under control of a tetracycline-responsive promoter demonstrated that TGFbeta prevented stabilization of KC mRNA, in response to LPS but did not alter KC mRNA half-life directly. KC mRNA stabilization by LPS was dependent on activation of p38 mitogen-activated protein kinase (MAPK) activity, and TGFbeta treatment inhibited p38 MAPK activation. These findings support the hypothesis that TGFbeta-mediated suppression of chemokine gene expression involves antagonism of LPS-stimulated KC mRNA stabilization via inhibition of p38 MAPK.

Animals↗
PubMed2000

Hypoxia-induced regulation of mRNA stability.

Because molecular oxygen is essential for generating cellular energy in aerobic organisms, and because survival depends on this fundamental requirement for oxygen, all higher organisms have evolved numerous diversely regulated mechanisms to detect and respond to potentially life-threatening occurrences of decreased oxygen availability (hypoxia). While the oxygen-dependent regulation of gene expression involves both transcriptional- and post-transcriptional mechanisms, investigations have focused mainly on mechanisms working at the transcriptional level. In this review, the focus is on a growing body of work that looks at post-transcriptional mechanisms acting at a level of mRNA stability.

Animals↗
PubMed2006

15-Deoxy-Delta12,14-prostaglandin J(2) induces death receptor 5 expression through mRNA stabilization independently of PPARgamma and potentiates TRAIL-induced apoptosis.

15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), the terminal derivative of the PGJ series, is emerging as a potent antineoplastic agent among cyclopentenone prostaglandins derivatives and also known as the endogenous ligand of peroxisome proliferator-activated receptor gamma (PPARgamma). On the other hand, death receptor 5 (DR5) is a specific receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is one of the most promising candidates for new cancer therapeutics. Here, we report that 15d-PGJ(2) induces DR5 expression at both mRNA and protein levels, resulting in the synergistic sensitization of TRAIL-induced apoptosis in human neoplastic cells, such as Jurkat human leukemia cells or PC3 human prostate cancer cells. 15d-PGJ(2) significantly increased DR5 mRNA stability, whereas it did not activate DR5 promoter activity. Synthetic PPARgamma agonists, such as pioglitazone or rosiglitazone, did not mimic the DR5-inducing effects of 15d-PGJ(2), and a potent PPARgamma inhibitor GW9662 failed to block DR5 induction by 15d-PGJ(2), suggesting PPARgamma-independent mechanisms. Cotreatment with 15d-PGJ(2) and TRAIL enhanced the sequential activation of caspase-8, caspase-10, caspase-9, caspase-3, and Bid. DR5/Fc chimera protein, zVAD-fmk pancaspase inhibitor, and caspase-8 inhibitor efficiently blocked the activation of these apoptotic signal mediators and the induction of apoptotic cell death enhanced by cotreatment with 15d-PGJ(2) and TRAIL. Moreover, a double-stranded small interfering RNA targeting DR5 gene, which suppressed DR5 up-regulation by 15d-PGJ(2), significantly attenuated apoptosis induced by cotreatment with 15d-PGJ(2) and TRAIL. These results suggest that 15d-PGJ(2) is a potent sensitizer of TRAIL-mediated cancer therapeutics through DR5 up-regulation.

Amino Acid Chloromethyl Ketones↗