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At least 1,297 records · Page 72Linked to original sources
PubMed2002

Regulation of endothelial matrix metalloproteinase-2 by hypoxia/reoxygenation.

Among the consequences resulting from the exposure of endothelial cells (ECs) to ischemia/reperfusion is angiogenesis, involving degradation of vascular basement membrane and extracellular matrix. Matrix metalloproteinase (MMP)-2, a member of the MMP family, partakes in this process. MMP-2, secreted as a proenzyme, undergoes activation through interaction with membrane type (MT)1-MMP and the endogenous tissue inhibitor of MMPs (TIMP)-2. Although hypoxia and reoxygenation (H/R) are major constituents of ischemia/reperfusion processes, their direct effects on endothelial MMP-2 have been scarcely investigated. This study examined the in vitro effects of H/R on human macrovascular ECs (EAhy 926). The level of MMP-2 mRNA (Northern blot) and protein (zymography, ELISA) and the mRNA of its activator (MT1-MMP) and inhibitor (TIMP-2) were analyzed. Short (6-hour) hypoxia inhibited the mRNA expression of MMP-2, MT1-MMP, and TIMP-2, culminating in reduced latent and active MMP-2 protein. Prolonged (24-hour) hypoxia further suppressed MT1-MMP and TIMP-2 mRNA, whereas it enhanced MMP-2 mRNA and enzyme secretion (after 48-hour hypoxia). Reoxygenation did not influence the inhibited TIMP-2 but upregulated MMP-2 and MT1-MMP mRNA expression, leading to enhanced secretion of active MMP-2 protein. These results demonstrate H/R-mediated modulation of EC MMP-2 at both transcriptional and posttranscriptional levels. Prolonged hypoxia of ECs appears to enhance MMP-2 production and secretion, whereas reoxygenation further increases its level. These H/R-mediated effects on MMPs have the potential of enabling EC migration and possible angiogenesis.

Blotting, Northern↗
PubMed2002

Inhibitors of histone deacetylation downregulate the expression of endothelial nitric oxide synthase and compromise endothelial cell function in vasorelaxation and angiogenesis.

The histone deacetylase (HDAC) inhibitor trichostatin A (TSA) inhibits hypoxia-stimulated angiogenesis. Endothelial nitric oxide synthase (eNOS)-derived NO is central to angiogenesis signaling in endothelial cells (ECs). We hypothesized that the HDAC-dependent regulation of angiogenesis may involve a modulatory effect on eNOS expression. The HDAC inhibitors TSA, butyric acid (BuA), and MS-275 time- and concentration-dependently suppressed eNOS protein levels to 41+/-2%, 46+/-12%, and 40+/-12% of control, respectively. In parallel, TSA and BuA also downregulated eNOS mRNA expression to 21+/-4% and 37+/-4% of control. TSA also attenuated the NO-dependent relaxation of porcine coronary arteries (P<0.0001, TSA 1 micromol/L) and prevented tube formation in a human angiogenesis assay. Although vascular endothelial growth factor substitution did not compensate for the inhibitory effect of TSA, exogenous NO reversed the inhibition of angiogenesis by TSA. To address the underlying signaling mechanism, we characterized the effect of TSA on eNOS gene transcription and mRNA half-life. Although TSA decreased both eNOS protein and mRNA levels, TSA paradoxically enhanced the activity of the eNOS promoter, and did not alter the eNOS transcription rate in nuclear run-on experiments, suggesting that TSA posttranscriptionally targets eNOS mRNA. These data indicate that HDAC-dependent mechanisms contribute to the regulation of eNOS expression in ECs.

Animals↗
PubMed2005

Calreticulin destabilizes glucose transporter-1 mRNA in vascular endothelial and smooth muscle cells under high-glucose conditions.

Substrate autoregulation of glucose transporter-1 (GLUT-1) mRNA and protein expression provides vascular endothelial and smooth muscle cells a sensitive mechanism to adapt their rate of glucose transport in response to changing glycemic conditions. Hyperglycemia-induced downregulation of glucose transport is particularly important in protecting these cells against an excessive influx of glucose and consequently increased intracellular protein glycation and generation of free radicals; both are detrimental in the development of vascular disease in diabetes. We aimed to investigate the molecular mechanism of high glucose-induced downregulation of GLUT-1 mRNA expression in primary bovine aortic vascular endothelial (VEC) and smooth muscle (VSMC) cell cultures. Using RNA mobility shift, UV cross-linking, and in vitro degradation assays, followed by mass-spectrometric analysis, we identified calreticulin as a specific destabilizing trans-acting factor that binds to a 10-nucleotide cis-acting element (CAE(2181-2190)) in the 3'-untranslated region of GLUT-1 mRNA. Pure calreticulin accelerated the rate of GLUT-1 mRNA-probe degradation in vitro, whereas overexpression of calreticulin in vascular cells decreased significantly the total cell content of GLUT-1 mRNA and protein. The expression of calreticulin was augmented in vascular cells exposed to high glucose in comparison with low-glucose conditions. Similarly, increased expression of calreticulin was observed in aortae of diabetic Psammomys obesus in comparison with normoglycemic controls. These data suggest that CAE(2181-2190)-calreticulin complex, which is formed in VSMC and VEC exposed to hyperglycemic conditions, renders GLUT-1 mRNA susceptible to degradation. This interaction underlies the process of downregulation of glucose transport in vascular cells under high-glucose conditions.

3' Untranslated Regions↗
PubMed2000

Transcriptional and posttranscriptional regulation of endothelial nitric oxide synthase expression by hydrogen peroxide.

Diverse stimuli, including shear stress, cyclic strain, oxidized LDL, hyperglycemia, and cell growth, modulate endothelial nitric oxide synthase (eNOS) expression. Although seemingly unrelated, these may all alter cellular redox state, suggesting that reactive oxygen intermediates might modulate eNOS expression. The present study was designed to test this hypothesis. Exposure of bovine aortic endothelial cells for 24 hours to paraquat, a superoxide (O(2)(-*))-generating compound, did not affect eNOS mRNA levels. However, cotreatment with paraquat and either Cu(2+)/Zn(2+) superoxide dismutase or the superoxide dismutase mimetic tetrakis(4-benzoic acid)porphyrin chloride increased eNOS mRNA by 2.3- and 2.2-fold, respectively, implicating a role for H(2)O(2). Direct addition of 100 and 150 micromol/L H(2)O(2) caused increases in bovine aortic endothelial cell eNOS mRNA that were dependent on concentration (ie, 3.1- and 5.2-fold increases) and time, and elevated eNOS protein expression and enzyme activity, accordingly. Nuclear run-on and 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole-chase studies showed that H(2)O(2) caused a 3.0-fold increase in eNOS gene transcription and a 2.8-fold increase in eNOS mRNA half-life. Induction of eNOS by H(2)O(2) was not affected by the hydroxyl radical scavenger DMSO, mannitol, or N-tert-butyl-alpha-phenylnitrone, but it was inhibited by the antioxidants N-acetylcysteine, ebselen, and exogenously added catalase. Unlike H(2)O(2), the 4.0-fold induction of eNOS by shear stress (15 dyne/cm(2) for 6 hours) was not inhibited by N-acetylcysteine or exogenous catalase. In conclusion, H(2)O(2) increases eNOS expression through transcriptional and post-transcriptional mechanisms. Although H(2)O(2) does not mediate shear-dependent eNOS regulation, it is likely to be involved in regulation of eNOS expression in response to other physiological and/or pathophysiological stimuli.

Animals↗
PubMed2001

Angiotensin AT(1) and AT(2) receptors differentially regulate angiopoietin-2 and vascular endothelial growth factor expression and angiogenesis by modulating heparin binding-epidermal growth factor (EGF)-mediated EGF receptor transactivation.

Angiotensin II (Ang II)-mediated signals are transmitted via heparin binding epidermal growth factor (EGF)-like growth factor (HB-EGF) release followed by transactivation of EGF receptor (EGFR). Although Ang II and HB-EGF induce angiogenesis, their link to the angiopoietin (Ang)-Tie2 system remains undefined. We tested the effects of Ang II on Ang1, Ang2, or Tie2 expression in cardiac microvascular endothelial cells expressing the Ang II receptors AT(1) and AT(2). Ang II significantly induced Ang2 mRNA accumulations without affecting Ang1 or Tie2 expression, which was inhibited by protein kinase C inhibitors and by intracellular Ca(2+) chelating agents. Ang II transactivated EGFR via AT(1), and inhibition of EGFR abolished the induction of Ang2. Ang II caused processing of pro-HB-EGF in a metalloproteinase-dependent manner to stimulate maturation and release of HB-EGF. Neutralizing anti-HB-EGF antibody blocked EGFR phosphorylation by Ang II. Ang II also upregulated vascular endothelial growth factor (VEGF) expression in an HB-EGF/EGFR-dependent manner. AT(2) inhibited AT(1)-mediated Ang2 expression and phosphorylation of EGFR. In an in vivo corneal assay, AT(1) induced angiogenesis in an HB-EGF-dependent manner and enhanced the angiogenic activity of VEGF. Although neither Ang2 nor Ang1 alone induced angiogenesis, soluble Tie2-Fc that binds to angiopoietins attenuated AT(1)-mediated angiogenesis. These findings suggested that (1) Ang II induces Ang2 and VEGF expression without affecting Ang1 or Tie2 and (2) AT(1) stimulates processing of pro-HB-EGF by metalloproteinases, and the released HB-EGF transactivates EGFR to induce angiogenesis via the combined effect of Ang2 and VEGF, whereas AT(2) attenuates them by blocking EGFR phosphorylation. Thus, Ang II is involved in the VEGF-Ang-Tie2 system via HB-EGF-mediated EGFR transactivation, and this link should be considerable in pathological conditions in which collateral blood flow is required.

Angiopoietin-1↗
PubMed2001

Platelet-derived growth factor promotes the expression of peroxisome proliferator-activated receptor gamma in vascular smooth muscle cells by a phosphatidylinositol 3-kinase/Akt signaling pathway.

Vascular diseases such as atherosclerosis are characterized by abnormal accumulation of vascular smooth muscle cells (VSMCs) within the intimal lining. The intimal VSMCs exhibit an increased expression of peroxisome proliferator-activated receptor gamma (PPARgamma), and the administration of pharmacological PPARgamma agonists attenuates vascular lesion formation. The factors that regulate PPARgamma expression in the vasculature are poorly defined. Here we report that platelet-derived growth factor (PDGF) upregulates PPARgamma by the phosphatidylinositol 3-kinase (PI3-kinase)/Akt signaling pathway. Using Northern-blotting and Western-blotting analyses, we observed that the levels of PPARgamma mRNA and protein were increased by 2- to 3.5-fold in human aortic smooth muscle cells (HASMCs) treated with PDGF (20 ng/mL). This was abolished by preincubation of HASMCs with a PI3-kinase inhibitor (LY294002, 50 micromol/L), and partially inhibited by a MEK1 inhibitor (U0126, 10 micromol/L), but not affected by a p38 kinase inhibitor (SB202190, 10 micromol/L). In addition, overexpression of the dominant-negative p85 subunit of PI3-kinase or Akt proteins blocked the PDGF-induced PPARgamma expression. Taken together, our results suggest that PDGF induces PPARgamma expression in VSMCs by a PI3-kinase/Akt signaling pathway. The characterization of factors and signaling pathways that modulate PPARgamma expression in VSMCs may have important implications for understanding the pathogenesis of vascular diseases.

Aorta↗
PubMed1995

Sheep lung cytochrome P4501A1 (CYP1A1): cDNA cloning and transcriptional regulation by oxygen tension.

Lung cytochrome P450 activity has been linked to neoplasia and may produce reactive oxidant species and potent arachidonic acid metabolites. In lamb lung, oxygen breathing increases lung P450 activity, and inhibition of lung cytochrome P450 activity reduces oxygen-induced lung injury. The P4501A1 (CYP1A1) isozyme is present in many lung cells, including endothelial cells, and may therefore be involved in the pathogenesis of hyperoxic injury to microvascular endothelium. Therefore, to test the hypothesis that oxygen regulates P4501A1 gene expression in the lung, we cloned the sheep P4501A1 cDNA, and examined its regulation by oxygen breathing significantly increased lung P4501A1 RNA levels and that this increase preceded the increase in isozyme activity. Oxygen exposure also promptly increased P4501A1 RNA levels in cultured lamb lung microvascular endothelial cells but not in endothelial cells isolated from the main pulmonary artery or in lung smooth muscle cells. The oxygen-stimulated increase in P4501A1 RNA levels was not serum dependent, was unaffected by cycloheximide treatment, and could not be mimicked by treatment of the cells with oxygenated medium, conditioned medium, or by chemical oxidants. By nuclear run-on assay in cultured lung endothelial cells, oxygen increased the transcription rate of P4501A1 by almost fourfold after 90 min of oxygen exposure but had no significant effect on P4501A1 RNA stability. We conclude that oxygen tension, but not chemical oxidants, increases P4501A1 gene expression pretranslationally in lung microvascular endothelial cells. We speculate that oxygen induction of P450 activity in these cells may contribute to microvascular injury during oxygen breathing.

Animals↗
PubMed2001

Merged screening for human immunodeficiency virus Tat and Rev inhibitors.

In addition to "conventional" drug discovery targets used in modern strategies, mainly focusing on proteins, recent insights into gene regulation as a novel drug concept have begun to invite the targeting of biomolecular interactions between proteins and RNA. Because two protein-RNA interactions (Tat and trans-activation-responsive element, Rev and Rev-responsive element) are essential for any productive replication of human immunodeficiency virus, this important human pathogen was used as a model system for our studies. The design of a fluorescence-based high throughput assay, in which both targets were presented in the same vessel, enabled us to simultaneously interrogate two characteristics of a potential inhibitor: potency of interference and selectivity toward each of the interactions. Although related systems have been reported for several DNA binders, an extension into interference with transcription events would open a new dimension of cellular regulation. Here we describe the setup of the screening assay for over 110,000 compounds as well as a primary characterization of identified hits. The assay's characteristics demonstrate that a microwell-based dual screening system for RNA binders may add a powerful tool to modern drug discovery.

Base Sequence↗
PubMed2002

Internalization of circulating apoptotic cells by splenic marginal zone dendritic cells: dependence on complement receptors and effect on cytokine production.

Under steady-state conditions, internalization of self-antigens embodied in apoptotic cells by dendritic cells (DCs) resident in peripheral tissue followed by DC migration and presentation of self-peptides to T cells in secondary lymphoid organs are key steps for induction and maintenance of peripheral T-cell tolerance. We show here that, besides this traffic of apoptotic cells mediated by peripheral tissue-resident DCs, splenic marginal zone DCs rapidly ingest circulating apoptotic leukocytes, process apoptotic cell-derived peptides into major histocompatibility complex class II (MHC-II) molecules, and acquire CD8alpha during their mobilization to T-cell areas of splenic follicles. Because apoptotic cells activate complement and some complement factors are opsonins for phagocytosis and play roles in the maintenance of peripheral tolerance, we investigated the role of complement receptors (CRs) in relation to phagocytosis of apoptotic cells by DCs. Apoptotic cell uptake by marginal zone DCs was mediated in part via CR3 (CD11b/CD18) and, to a lesser extent, CR4 (CD11c/CD18) and was reduced significantly in vivo in hypocomplementemic animals. Following phagocytosis of apoptotic cells, DCs exhibited decreased levels of mRNA and secretion of the proinflammatory cytokines interleukin 1alpha (IL-1alpha), IL-1beta, IL-6, IL-12p70, and tumor necrosis factor alpha (TNF-alpha), without effect on the anti-inflammatory mediator transforming growth factor beta1 (TGF-beta1). This selective inhibitory effect was at least partially mediated through C3bi-CD11b/CD18 interaction. Characterization of apoptotic cell/DC interaction and its outcome provides insight into the mechanisms by which apoptotic cells affect DC function without disrupting peripheral tolerance.

Animals↗
PubMed2006

FGF2 posttranscriptionally down-regulates expression of SDF1 in bone marrow stromal cells through FGFR1 IIIc.

The chemokine stromal cell-derived factor-1 (SDF-1) is constitutively expressed by bone marrow stromal cells and plays key roles in hematopoiesis. Fibroblast growth factor 2 (FGF2), a member of the FGF family that plays important roles in developmental morphogenic processes, is abnormally elevated in the bone marrow from patients with clonal myeloid disorders and other disorders where normal hematopoiesis is impaired. Here, we report that FGF2 reduces SDF-1 secretion and protein content in bone marrow stromal cells. By inhibiting SDF-1 production, FGF2 compromises stromal cell support of hematopoietic progenitor cells. Reverse-transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that bone marrow stromal cells express 5 FGF receptors (FGFRs) among the 7 known FGFR subtypes. Blocking experiments identified FGFR1 IIIc as the receptor mediating FGF2 inhibition of SDF-1 expression in bone marrow stromal cells. Analysis of the mechanisms underlying FGF2 inhibition of SDF-1 production in bone marrow stromal cells revealed that FGF2 reduces the SDF-1 mRNA content by posttranscriptionally accelerating SDF-1 mRNA decay. Thus, we identify FGF2 as an inhibitor of SDF-1 production in bone marrow stromal cells and a regulator of stromal cell supportive functions for hematopoietic progenitor cells.

Animals↗
PubMed2002

Abnormally spliced beta-globin mRNAs: a single point mutation generates transcripts sensitive and insensitive to nonsense-mediated mRNA decay.

Nonsense-mediated mRNA decay (NMD) represents a phylogenetically widely conserved splicing- and translation-dependent mechanism that eliminates transcripts with premature translation stop codons and suppresses the accumulation of C-terminally truncated peptides. Elimination of frameshifted transcripts that result from faulty splicing may be an important function of NMD. To test this hypothesis directly, this study used the IVS1 + 5 G>A thalassemia mutation of the human beta-globin gene as a model system. We generated beta-globin gene constructs with this mutation and an iron-responsive element in the 5' untranslated region, which allowed specific experimental activation and inactivation of translation and, hence, NMD of this transcript. Premessenger RNAs with IVS1 + 5 G>A were spliced at normal sites and cryptic sites, enabling a direct comparison of the effect of NMD on the accumulation of normal and frameshifted messenger RNAs. In transfected HeLa cells, the predominant frameshifted transcript was degraded under conditions of active NMD, whereas accumulation to high levels occurred under conditions of specifically disabled NMD, thereby indicating an important physiologic function of NMD in the control of the splicing process. An unexpected finding was that accumulation of a second aberrant transcript remained unaffected by NMD. The IVS1 + 5 G>A mutation thus revealed the presence of an unknown cis-acting determinant that influences the NMD sensitivity of a putative NMD substrate. It can therefore serve as a useful tool for defining the mechanisms that permit specific transcripts to circumvent the NMD pathway.

Codon, Nonsense↗
PubMed2002

Epstein-Barr virus reactivation after superinfection of the BJAB-B1 and P3HR-1 cell lines with cytomegalovirus.

BACKGROUND: Studies examining herpesvirus-herpesvirus (cytomegalovirus (CMV)-Epstein-Barr virus (EBV)) interactions are limited, and many of the studies have been clinical observations suggesting such an interaction exists. This report aims to examine the in vitro susceptibilities of BJAB-B1 and P3HR-1 cells (EBV positive Burkitt's lymphoma B-cell lines) to a CMV superinfection; and show that EBV reactivation occurs after CMV superinfects these cell lines. RESULTS: The BJAB-B1 and P3HR-1 cells were observed to be susceptible to a CMV superinfection by detecting the major immediate early (MIE) viral transcript and protein (p52) expression. The BZLF1 transcript was observed in both cell lines superinfected with CMV, indicating EBV reactivation. BZLF1 protein was observed in the BJAB-B1 cells. Antigen detection was not performed in the P3HR-1 cells. CONCLUSION: The results from the in vitro superinfections support the in vivo studies suggesting a CMV infection is related to an EBV reactivation and suggests that CMV may be important as a co-factor in EBV pathogenesis in the immunocompromised patient.

Antigens, Viral↗
PubMed2004

Short-term cytotoxic effects and long-term instability of RNAi delivered using lentiviral vectors.

BACKGROUND: RNA interference (RNAi) can potently reduce target gene expression in mammalian cells and is in wide use for loss-of-function studies. Several recent reports have demonstrated that short double-stranded RNAs (dsRNAs), used to mediate RNAi, can also induce an interferon-based response resulting in changes in the expression of many interferon-responsive genes. Off-target gene silencing has also been described, bringing into question the validity of certain RNAi-based approaches for studying gene function. We have targeted the plasminogen activator inhibitor-2 (PAI-2 or SERPINB2) mRNA using lentiviral vectors for delivery of U6 promoter-driven PAI-2-targeted short hairpin RNA (shRNA) expression. PAI-2 is reported to have anti-apoptotic activity, thus reduction of endogenous expression may be expected to make cells more sensitive to programmed cell death. RESULTS: As expected, we encountered a cytotoxic phenotype when targeting the PAI-2 mRNA with vector-derived shRNA. However, this predicted phenotype was a potent non-specific effect of shRNA expression, as functional overexpression of the target protein failed to rescue the phenotype. By decreasing the shRNA length or modifying its sequence we maintained PAI-2 silencing and reduced, but did not eliminate, cytotoxicity. ShRNA of 21 complementary nucleotides (21 mers) or more increased expression of the oligoadenylate synthase-1 (OAS1) interferon-responsive gene. 19 mer shRNA had no effect on OAS1 expression but long-term selective pressure on cell growth was observed. By lowering lentiviral vector titre we were able to reduce both expression of shRNA and induction of OAS1, without a major impact on the efficacy of gene silencing. CONCLUSIONS: Our data demonstrate a rapid cytotoxic effect of shRNAs expressed in human tumor cell lines. There appears to be a cut-off of 21 complementary nucleotides below which there is no interferon response while target gene silencing is maintained. Cytotoxicity or OAS1 induction could be reduced by changing shRNA sequence or vector titre, but stable gene silencing could not be maintained in extended cell culture despite persistent marker gene expression from the RNAi-inducing transgene cassette. These results underscore the necessity of careful controls for immediate and long-term RNAi use in mammalian cell systems.

2',5'-Oligoadenylate Synthetase↗
PubMed2006

Small interfering RNA targeted to stem-loop II of the 5' untranslated region effectively inhibits expression of six HCV genotypes.

BACKGROUND: The antiviral action of interferon alpha targets the 5' untranslated region (UTR) used by hepatitis C virus (HCV) to translate protein by an internal ribosome entry site (IRES) mechanism. Although this sequence is highly conserved among different clinical strains, approximately half of chronically infected hepatitis C patients do not respond to interferon therapy. Therefore, development of small interfering RNA (siRNA) targeted to the 5'UTR to inhibit IRES mediated translation may represent an alternative approach that could circumvent the problem of interferon resistance. RESULTS: Four different plasmid constructs were prepared for intracellular delivery of siRNAs targeting the stem loop II-III of HCV 5' UTR. The effect of siRNA production on IRES mediated translation was investigated using chimeric clones between the gene for green fluorescence protein (GFP) and IRES sequences of six different HCV genotypes. The siRNA targeted to stem loop II effectively mediated degradation of HCV IRES mRNA and inhibited GFP expression in the case of six different HCV genotypes, where as siRNAs targeted to stem loop III did not. Furthermore, intracytoplasmic expression of siRNA into transfected Huh-7 cells efficiently degraded HCV genomic RNA and inhibited core protein expression from infectious full-length infectious clones HCV 1a and HCV 1b strains. CONCLUSION: These in vitro studies suggest that siRNA targeted to stem-loop II is highly effective inhibiting IRES mediated translation of the major genotypes of HCV. Stem-loop II siRNA may be a good target for developing an intracellular immunization strategy based antiviral therapy to inhibit hepatitis C virus strains that are not inhibited by interferon.

5' Untranslated Regions↗
PubMed2001

Genomic-scale measurement of mRNA turnover and the mechanisms of action of the anti-cancer drug flavopiridol.

BACKGROUND: Flavopiridol, a flavonoid currently in cancer clinical trials, inhibits cyclin-dependent kinases (CDKs) by competitively blocking their ATP-binding pocket. However, the mechanism of action of flavopiridol as an anti-cancer agent has not been fully elucidated. RESULTS: Using DNA microarrays, we found that flavopiridol inhibited gene expression broadly, in contrast to two other CDK inhibitors, roscovitine and 9-nitropaullone. The gene expression profile of flavopiridol closely resembled the profiles of two transcription inhibitors, actinomycin D and 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB), suggesting that flavopiridol inhibits transcription globally. We were therefore able to use flavopiridol to measure mRNA turnover rates comprehensively and we found that different functional classes of genes had distinct distributions of mRNA turnover rates. In particular, genes encoding apoptosis regulators frequently had very short half-lives, as did several genes encoding key cell-cycle regulators. Strikingly, genes that were transcriptionally inducible were disproportionately represented in the class of genes with rapid mRNA turnover. CONCLUSIONS: The present genomic-scale measurement of mRNA turnover uncovered a regulatory logic that links gene function with mRNA half-life. The observation that transcriptionally inducible genes often have short mRNA half-lives demonstrates that cells have a coordinated strategy to rapidly modulate the mRNA levels of these genes. In addition, the present results suggest that flavopiridol may be more effective against types of cancer that are highly dependent on genes with unstable mRNAs.

Antineoplastic Agents↗
PubMed2002

Untranslated regions of mRNAs.

Gene expression is finely regulated at the post-transcriptional level. Features of the untranslated regions of mRNAs that control their translation, degradation and localization include stem-loop structures, upstream initiation codons and open reading frames, internal ribosome entry sites and various cis-acting elements that are bound by RNA-binding proteins.

Animals↗