Regulation Of Gene Expression In Cells Research Articles

EBV-encoded miRNAs

The Epstein–Barr virus (EBV) is an oncogenic Herpes virus involved in the induction of a variety of human tumours. It was the first virus found to encode microRNAs (miRNAs). MiRNAs are short, non-coding RNAs that in most cases negatively regulate gene expression at the post-transcriptional level. EBV-transformed cells express at least 44 mature viral miRNAs that target viral and cellular genes. In addition, EBV-infection severely deregulates the miRNA profile of the host cell. The presently available information indicates that the virus uses its miRNAs to inhibit the apoptotic response of the infected cell as a means to establish a latent infection. Likewise, EBV-encoded miRNAs interfere in the expression of viral genes in order to mask the infected cell from the immune response. Cellular targets of viral miRNAs are involved in protein traffic within the cell and regulate innate immunity. MiRNA profiling of diffuse large B-cell lymphoma (DLBCL) and nasal NK/T-cell lymphoma (NKTL) showed that only 2% of the miRNAs are derived from the virus, while viral miRNAs comprise up to 20% of the total miRNA in nasopharyngeal carcinoma (NPC) and probably contribute to the formation or maintenance of NPC. The presence of viral miRNAs in exosomes raises the fascinating possibility that virus-infected cells regulate gene expression in the surrounding tissue to avert destruction by the immune system. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation.

Structure and function of a transcriptional network activated by the MAPK Hog1.

Cells regulate gene expression using a complex network of signaling pathways, transcription factors and promoters. To gain insight into the structure and function of these networks, we analyzed gene expression in single- and multiple-mutant strains to build a quantitative model of the Hog1 MAPK-dependent osmotic stress response in budding yeast. Our model reveals that the Hog1 and general stress (Msn2/4) pathways interact, at both the signaling and promoter level, to integrate information and create a context-dependent response. This study lays out a path to identifying and characterizing the role of signal integration and processing in other gene regulatory networks.

EIF4E, the mRNA cap-binding protein: from basic discovery to translational researchThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB — Systems and Chemical Biology, and has undergone the Journal's usual peer review process.

Translational control is an important strategy by which eukaryotic cells regulate gene expression. Translation is the last step in the flow of genetic information, and regulation at this level allows an immediate and rapid response to changes under physiological conditions. Because the processes of mRNA biogenesis, including transcription, splicing, and export to the cytoplasm, are time consuming, the use of pre-existing mRNAs via the control of translation is advantageous in many circumstances. A prime target of translational control is the initiation factor eIF4E, which recognizes the m7GpppN cap structure present at the 5' end of all nuclear transcribed eukaryotic mRNAs. In this article I describe the discovery of eIF4E, its mechanism of action in translation initiation, and its role in the control of cancer and innate immunity.

RNA Recognition and Cleavage by Sequence-Specific Endoribonucleases

Inactivation of RNA molecules by sequence-specific endoribonucleolytic cleavage is a subtle mechanism by which cells regulate gene expression. Sequence-specific endoribonucleases can recognize and cleave particular phosphodiester bonds confined within hundreds/thousands of chemically similar bonds. Here, we present a comparative analysis of the mechanisms used by endoribonucleases to select and cleave their target RNA molecules. This analysis is based on the very recent molecular details obtained from the structural and/or biochemical studies of nine sequence-specific ribonucleases that target messenger, ribosomal, and transfer RNA molecules. This analysis shows that despite the absence of sequence homologies and the wide diversity of biological sources (prokaryotes, archaea and eukaryotes), the sequence-specific ribonucleases studied here adopt limited structural folds, catalyze their cleavage reactions using a common chemistry and involve a very limited set of amino acids for both RNA binding and processing.

Differential regulation of ARE-mediated TNFα and IL-1β mRNA stability by lipopolysaccharide in RAW264.7 cells

Messenger RNA degradation is a mechanism by which eukaryotic cells regulate gene expression and influence cell growth and differentiation. Many protooncogene, cytokine, and growth factor RNAs contain AU-rich element (AREs) in the 3′untranslated regions which enable them to be targeted for rapid degradation. To investigate the mechanism of ARE-mediated RNA stability, we demonstrate the expression and regulation of TNFα and IL-1β mRNAs in LPS-stimulated macrophages. TNFα mRNA was rapidly induced by LPS and showed short half-life at 2-h induction, whereas IL-1β mRNA was induced slowly and had longer half-life. Electrophoretic mobility shift assays showed that the LPS-induced destabilization factor tristetraprolin (TTP) could bind to TNFα ARE with higher affinity than to IL-1β ARE. HuR was identified to interact with TNFα ARE to exert RNA stabilization activity. The expression and phosphorylation of TTP could be activated by p38 MAPK pathway during LPS stimulation. Moreover, ectopic expression with TTP and kinases in p38 pathway followed by biochemical assays showed that the activation of p38 pathway resulted in the phosphorylation of TTP and a decrease in its RNA-binding activity. The ARE-containing reporter assay presented that the p38 signal could reverse the inhibitory activity of TTP on IL-1β ARE but not on TNFα ARE. The present results indicate that the heterogeneity of AREs from TNFα and IL-1β could reflect distinct ARE-binding proteins to modulate their RNA expression.

Action at a Distance

Ways in which cells regulate gene expression are still being discussed. The picture of all regulatory regions, strung out, like beads on a string, upstream from and in close proximity to the transcribed region of DNA, has given place to a much more dynamic picture whereby highly structured protein

Negative autoregulation speeds the response times of transcription networks.

Cells regulate gene expression using networks of transcription interactions; it is of interest to discover the principles that govern the dynamical behavior of such networks. An important characteristic of these systems is the rise-time: the delay from the initiation of production until half maximal product concentration is reached. Here we employ synthetic gene circuits in Escherichia coli to measure the rise-times of non-self-regulated and of negatively autoregulated transcription units. Non-self-regulated units have a rise-time of one cell-cycle. We demonstrate experimentally that negative autoregulation feedback (also termed autogenous control) reduces the rise-time to about one fifth of a cell-cycle. This agrees with an analytical solution of a mathematical model for negative autoregulation. This may help in understanding the function of negative autoregulation, which appears in over 40% of known transcription factors in E.coli.

Methylation, gene expression and the chromatin connection in cancer (review)

The mechanisms by which cells regulate gene expression are often altered in tumors. Modulating aspects of the components responsible for the nuclear packaging of DNA is one means by which the cell can control transcription, either by packaging the DNA such that access to specific sites of transcription is blocked or by modifying the DNA itself to prevent transcription factor binding. One such DNA modification is the methylation of cytosines. In addition, histone acetylation status has been linked recently through a large number of studies to the regulation of gene expression. Expressed genes are located in highly acetylated chromatin. The acetylation status of nucleosomes (the basic packaging unit of chromatin), is regulated by a group of enzymes, histone acetyltransferases (HATs), and histone deacetylases (HDACs). These two elements, methylation and histone acetylation have also been linked together, whereby methylation is used to direct gene repression through a histone deacetylase complex. Methylation, HATs, and HDACs have been shown to be altered in tumors. We present an overview of the current knowledge surrounding these elements in cancer, and in the final sections describe the likelihood of alterations of the histone modifying apparatus in hepatocellular carcinoma.

DNA methylation, chromatin structure and the regulation of gene expression.

It is still not clear how eukaryotic cells regulate gene expression during differentiation and in the differentiated state. There is increasing experimental evidence that this requires a wide spectrum of different cis- and trans-acting elements (for a review, see Wasylyk, 1988). One of the cis-functional elements, crucial for gene activation, is the change in the DNA methylation pattern. In mammalian cells methylation occurs exclusively at the cytosine residue in the CpG dinucleotide sequence.KeywordsThymidine Kinase GeneHistone OctamersHerpes Simplex Thymidine Kinase GeneChromatin FormationBlock Gene ExpressionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Translational control of gene expression in the human brain

1. Translational control is the regulation of protein synthesis as an alteration in the efficiency of mRNA translation and is a common mechanism by which cells regulate gene expression. 2. Alterations of total protein synthesis are often the responses of cells to various stress stimuli including starvation, viral infection, and heat shock. 3. Numerous specific genes including ferritin heavy chain, tubulin, vimentin and the 1ck proto-oncogene have also been shown to be under translational control. 4. Unlike cultured cells or intact organisms, the investigation of translational control in the human brain requires the measurement of components of protein synthesis, especially polysomes. Therefore, we have purified and characterized polysomes from human postmortem brain tissues and compared them to polysomes purified from the adult rat brain. 5. The yield (as A260 units per gram brain tissue), size (as number of ribosomes per message), translational efficiency (as amount protein synthesized per A260 unit), and ability to reinitiate (as amount of protein synthesis prevented by initiation inhibitors) were all significantly lower as exhibited by the human polysomes compared with the rat polysoraes. However, the human and rat polysomes synthesized similar polypeptides. 6. Thus, the human polysomes differed from the rat polysomes principally in the efficiency of mRNA translation which is likely due to the greatly reduced ability of the human polysomes to initiate protein synthesis.