PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “RNA Stability”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 883 records · Page 49Linked to original sources
PubMed2006

Applying nonsense-mediated mRNA decay research to the clinic: progress and challenges.

Premature termination codons (PTCs) are equivalent to nonsense sequences. They encode no amino acid, and their presence precludes the synthesis of full-length proteins. Furthermore, the resulting truncated proteins, if synthesized and stable, are likely to be non-functional or might even be deleterious to cellular metabolism. Approximately one third of genetic and acquired diseases are due to PTCs. In fact, PTCs are apt to cause at least some cases of all diseases that involve protein insufficiency. Cells have evolved a way to eliminate mRNAs that contain PTCs using a mechanism called nonsense-mediated mRNA decay (NMD). Here, we will review how to determine which PTCs elicit NMD, what is currently known about the mechanism of NMD, and additional information that is pertinent to establishing therapies for PTC-associated diseases.

Animals↗
PubMed2005

Expression of p53 in renal carcinoma cells is independent of pVHL.

Renal clear-cell carcinoma (RCC) is the predominant form of kidney cancer and is highly refractory to conventional anti-cancer therapies. The status of p53 tumor suppressor gene has been correlated with the efficacy of radio- and chemotherapies, where presence of mutant p53 is associated with reduced responsiveness to treatment. However, p53 itself is rarely mutated in RCC, rather suggesting that the p53 pathway might be compromized in RCC cells. In support of this notion, the transactivation property of normal p53 was shown to be repressed in various transformed kidney epithelial cells via an unknown dominant-negative mechanism. Mutation of the von Hippel-Lindau (VHL) gene causes familial VHL disease, which includes predisposition to RCC. Moreover, biallelic inactivation of VHL has been observed in the vast majority of sporadic RCC. Recently, the expression of pVHL in RCC cells was demonstrated to elevate the expression of p53 by inducing the binding of RNA-stabilizing protein HuR to the 3'untranslated region of p53 mRNA. Contrary to this finding, we report here that the reconstitution of a variety of VHL(-/-) RCC lines including 786-O, RCC4, and A498 or non-RCC cells with wild-type pVHL does not influence the expression of p53 and fails to induce p53-responsive gene p21CIP1/WAF1 or p53-responsive reporters. These results suggest that the expression of p53 in RCC cells is independent of pVHL.

Amino Acid Sequence↗
PubMed2006

The breast cancer susceptibility allele CHEK2*1100delC promotes genomic instability in a knock-in mouse model.

Allelic variants of CHEK2 contribute to an elevated risk for human breast cancer and possibly other cancer types. In particular, the CHEK2*1100delC polymorphic variant has been identified as a low-penetrance breast cancer susceptibility allele in breast cancer families with wild type BRCA1 and BRCA2. To better understand the molecular basis by which this allele increases risk for disease, we have generated a mouse in which the wild type CHEK2 (Chk2 in mouse) allele has been replaced with the 1100delC variant. Mouse embryo fibroblasts (MEFs) derived from these mice have an altered cell cycle profile in which a far greater proportion of cells are in S-phase and in G2 (4N) compared with wild type cells. The mutant cells show signs of spontaneous genomic instability as indicated by polyploidy and an increase in DNA double strand breaks.

Alleles↗
PubMed2006

Neuronal RNA granules: movers and makers.

RNA localization contributes to cell polarity and synaptic plasticity. Evidence will be discussed that RNA transport and local translation in neurons may be more intimately linked than originally thought. Second, neuronal RNA granules, originally defined as intermediates involved in mRNA transport, are much more diverse in their composition and functions than previously anticipated. We focus on three classes of RNA granules that include transport RNPs, stress granules, and P bodies and discuss their potential functions in RNA localization, microRNA-mediated translational regulation, and mRNA degradation.

Animals↗
PubMed2004

Regulation of transposition in bacteria.

Mobile genetic elements (MGEs) play a central role in the evolution of bacterial genomes. Transposable elements (TE: transposons and insertion sequences) represent an important group of these elements. Comprehension of the dynamics of genome evolution requires an understanding of how the activity of TEs is regulated and how their activity responds to the physiology of the host cell. This article presents an overview of the large range of, often astute, regulatory mechanisms, which have been adopted by TEs. These include mechanisms intrinsic to the element at the level of gene expression, the presence of key checkpoints in the recombination pathway and the intervention of host proteins which provide a TE/host interface. The multiplicity and interaction of these mechanisms clearly illustrates the importance of limiting transposition activity and underlines the compromise that has been reached between TE activity and the host genome. Finally, we consider how TE activity can shape the host genome.

Bacteria↗
PubMed2004

An enemy within: fly reconnaissance deploys an endonuclease to destroy nonsense-containing mRNA.

Quality-control mechanisms function in cells to ensure proper gene expression. Nonsense-mediated mRNA decay (NMD) is one such mechanism and it degrades abnormal mRNAs that contain a premature-termination codon. Although NMD is conserved in all eukaryotes that have been examined, it can manifest mechanistic differences in different organisms. A recent study using Drosophila melanogaster describes a new mechanistic twist to NMD.

Animals↗
PubMed2005

CUTting genetic noise by polyadenylation-induced RNA degradation.

Silencing of genomic regions in eukaryotes is thought to be the result of transcriptional repression. Recent results show that nuclear RNA degradation plays a major role in discarding RNA molecules with no obvious roles that are produced by cryptic RNA polymerase II transcription throughout the Saccharomyces cerevisiae genome. These cryptic transcripts are polyadenylated at their 3'-end by a poly(A) polymerase complex distinct from that used by the mRNA factory, which serves to tag these aberrant transcripts for nuclear degradation.

Genes, Fungal↗
PubMed2006

Pathways for mRNA localization in the cytoplasm.

Studies of the intracellular localization of mRNA have clearly demonstrated that certain subsets of mRNA are concentrated in discrete locations within the cytoplasm. Localization is one aspect of the post-transcriptional control of gene expression, and is intertwined with the translation and turnover of mRNA to achieve the goal of local protein production. Different mechanisms have been identified that enable localized mRNAs to target different subcellular compartments, and recent advances in understanding these pathways is reviewed here.

Animals↗
PubMed2004

Bringing the role of mRNA decay in the control of gene expression into focus.

The process of mRNA decay is integral to the post-transcriptional control of gene expression. The enzymes of the pathway have been identified, and now several laboratories have found that the mRNA decay machinery is localized to discrete cytoplasmic foci whose existence had not been suspected previously. In addition, we can now see that mRNA turnover is a means to coordinate gene expression, first through integration with control of transcription, export and translation of mRNAs, and second through enabling mRNAs involved in similar processes to decay at similar rates. These and other aspects of the field are discussed.

Cytoplasm↗
PubMed2006

Regulated translational bypass of stop codons in yeast.

Stop codons are used to signal the ribosome to terminate the decoding of an mRNA template. Recent studies on translation termination in the yeast Saccharomyces cerevisiae have not only enabled the identification of the key components of the termination machinery, but have also revealed several regulatory mechanisms that might enable the controlled synthesis of C-terminally extended polypeptides via stop-codon readthrough. These include both genetic and epigenetic mechanisms. Rather than being a translation 'error', stop-codon readthrough can have important effects on other cellular processes such as mRNA degradation and, in some cases, can confer a beneficial phenotype to the cell.

Codon, Terminator↗
PubMed2004

Derivation and function of small interfering RNAs and microRNAs.

Small interfering RNA (siRNA) duplexes are generally produced by Dicer cleavage of double-stranded RNAs of frequently exogenous origin and can induce the cleavage and degradation of mRNAs bearing an identical sequence. In contrast, microRNAs (miRNAs) are encoded within the eukaryotic genome as short RNA hairpin structures. While these pre-miRNAs are also processed by Dicer, mature miRNAs appear to function primarily by inhibiting the translation of mRNAs bearing multiple, partially mismatched target sites. Nevertheless, recent data argue that the posttranscriptional regulatory machinery utilized by siRNAs and miRNAs is largely or entirely identical. In this review, I will discuss recent progress in unraveling the RNA processing pathway utilized for the biosynthesis of mature miRNAs and argue that this pathway offers at least three distinct entry points for the functional expression of artificial siRNAs in vertebrate cells. While each of these entry points offers distinct advantages and disadvantages, they all have the potential to induce the effective knock-down of specific genes either in cell culture or in experimental animals.

MicroRNAs↗
PubMed2004

RNA silencing of rotavirus gene expression.

RNA interference (RNAi) is a double-stranded RNA (dsRNA)-triggered mechanism for suppressing gene expression, which is conserved in evolution and has emerged as a powerful tool to study gene function. Rotaviruses, the leading cause of severe diarrhea in young children, are formed by three concentric layers of protein, and a genome composed of 11 segments of dsRNA. Here, we show that the RNAi machinery can be triggered to silence rotavirus gene expression by sequence-specific short interfering RNAs (siRNAs). RNAi is also useful for the study of the virus-cell interactions, through the silencing of cellular genes that are potentially important for the replication of the virus. Interestingly, while the translation of mRNAs is readily stopped by the RNAi machinery, the viral transcripts involved in virus genome replication do not seem to be susceptible to RNAi. Since gene silencing by RNAi is very efficient and specific, this system could become a novel therapeutic approach for rotavirus and other virus infections, once efficient methods for in vivo delivery of siRNAs are developed. Although the use of RNAi as an antiviral therapeutic tool remains to be demonstrated, there is no doubt that this technology will influence drastically the way postgenomic virus research is conducted.

Gene Expression Regulation, Viral↗
PubMed2004

Control of HIV-1 replication by RNA interference.

Small interfering RNAs (siRNAs) have been shown to direct sequence-specific inhibition of gene expression in mammalian cells. siRNAs are RNA duplexes of 21-23 nucleotides (nts) with approximately 2nt 3' overhangs that can induce degradation of their homologous target mRNAs without interferon responses in mammalian cells. The degradation of the target occurs at the post-transcriptional level, meaning a post-transcriptional gene silencing (PTGS) mechanism called as RNA interference (RNAi). RNAi has emerged as an efficient method to inhibit gene expression in mammalian cells with increasingly successful cases of knockdown of many specific genes. Recent works have shown that the use of RNAi could inhibit HIV-1 replication by targeting viral or cellular genes. RNAi can be considered as a gene-specific therapeutic option for controlling HIV-1 replication. However, the control of HIV-1 replication has become complex because of the limited effectiveness of existing anti-HIV-1 agents and the high speed mutation rate of the HIV-1 genome. Careful assessments are required for the potential of RNAi as a gene therapy approach for controlling HIV-1 replication. This review will discuss the status of the science using RNAi for controlling HIV-1 replication and will describe possible problems for therapeutic applications of RNAi-mediated technologies for HIV-1 behind this novel mechanism.

Gene Expression Regulation, Viral↗
PubMed2004

RNA interference, arthropod-borne viruses, and mosquitoes.

RNA interference (RNAi) probably functions as an antiviral mechanism in most eukaryotic organisms. Variations in the activity of this antiviral pathway in mosquitoes could explain, in part, why some mosquitoes are competent vectors of medically important, arthropod-borne viruses (arboviruses) and others are not. There are three lines of evidence that show the RNAi pathway exists in Aedes species that transmit arboviruses. The first is that recombinant Sindbis viruses expressing a RNA fragment from a genetically unrelated dengue-2 virus (DENV-2) interfere with DENV-2 replication in Aedes aegypti mosquitoes by a mechanism similar to virus-induced gene silencing described in plants. The second is that transfection of C6/36 (Aedes albopictus) cells with either double-stranded RNA or synthetic small interfering RNAs derived from an arbovirus genome interferes with replication of the homologous virus. The third is that a hairpin DENV-2-specific RNA transcribed from a plasmid can generate virus-resistant C6/36 cells. We hypothesize that genetically modified mosquitoes can be generated that transcribe a flavivirus-specific dsRNA, triggering the RNAi response soon after ingestion of a blood meal. This could induce the RNAi pathway in the midgut prior to establishment of virus infection and profoundly change vector competence. Towards this goal, we are developing transgenic A. aegypti lines that are refractory to DENV by exploiting the RNAi pathway.

Animals↗
PubMed2004

RNA interference as a new biotechnological tool for the control of virus diseases in plants.

RNA silencing occurs in a wide variety of organisms, including protozoa, fungi, plants and animals and involves recognition of a target RNA and initiation of a sequence-specific RNA degradation pathway in the cytoplasm. In the last few years, there have been considerable advances in our understanding of post-transcriptional gene silencing (PTGS). This mechanism is conceived as a natural antiviral defense system in plants that is activated as a response to double-stranded RNA (dsRNA) formed during virus replication. To develop new approaches for plant protection against virus diseases based on PTGS we have expanded previous findings on RNA interference (RNAi) in animals by using dsRNA to specifically interfere with virus infection in plants. This approach differs from strategies based on transgenic expression of RNAs but still relies on PTGS as a means to achieve pathogen-derived resistance (PDR). Our findings suggest that exogenously supplied dsRNA could form the basis for the development of an environmentally safe, new biotechnological tool aimed at protecting crops against virus diseases, provided that some limitations of the current status of the approach could be overcome.

Biotechnology↗
PubMed2006

Selective degradation of transcripts during meiotic maturation of mouse oocytes.

There is massive destruction of transcripts during the maturation of mouse oocytes. The objective of this project was to identify and characterize the transcripts that are degraded versus those that are stable during the transcriptionally silent germinal vesicle (GV)-stage to metaphase II (MII)-stage transition using a microarray approach. A system for oocyte transcript amplification using both internal and 3'-poly(A) priming was utilized to minimize the impact of complex variations in transcript polyadenylation prevalent during this transition. Transcripts were identified and quantified using the Affymetrix Mouse Genome 430 v2.0 GeneChip. The significantly changed and stable transcripts were analyzed using Ingenuity Pathways Analysis and GenMAPP/MAPPFinder to characterize the biological themes underlying global changes in oocyte transcripts during maturation. It was concluded that the destruction of transcripts during the GV to MII transition is a selective rather than promiscuous process in mouse oocytes. In general, transcripts involved in processes that are associated with meiotic arrest at the GV-stage and the progression of oocyte maturation, such as oxidative phosphorylation, energy production, and protein synthesis and metabolism, were dramatically degraded. In contrast, transcripts encoding participants in signaling pathways essential for maintaining the unique characteristics of the MII-arrested oocyte, such as those involved in protein kinase pathways, were the most prominent among the stable transcripts.

Animals↗
PubMed2004

Recruitment of mRNA-destabilizing protein TIS11 to stress granules is mediated by its zinc finger domain.

TIS11, a member of the CCCH zinc finger protein family, was found to be distributed throughout cells with a preferential cytoplasmic localization when transiently expressed in COS-7 cells. Upon treatment with heat shock, TIS11 became localized in discrete particles in the cytoplasm of the transfectants. We showed the TIS11-positive particles to be stress granules (SGs), which are known to be formed in the cytoplasm of eukaryotic cells in response to environmental stresses. By deletion studies using the green fluorescent protein fusion system, we mapped a functional stress granule (SG) localization signal to a region containing two tandem repeats of the zinc finger motif of TIS11. Site-directed mutations of Tyr105/Tyr113, Gly109/Gly 114, and Phe119 in the first zinc finger motif diminished the ability of this TIS11 domain to direct SG localization. Importantly, when the zinc-chelating Cys residues in either the first or second zinc finger were mutated to Ala residues, the recruitment of the TIS11 zinc finger region to SG was significantly inhibited by the mutation and was completely abolished by the mutation in both zinc fingers. These results suggest that recruitment of TIS11 to heat shock-induced SG is governed by the tandem zinc finger domains of this protein.

Amino Acid Sequence↗