Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The completion of the human genome project has left researchers searching for an efficient method to study gene function in mammalian cells. RNA interference (RNAi) is an evolutionarily conserved post-transcriptional gene silencing (PTGS) mechanism mediated by double-stranded RNA (dsRNA). The dsRNA is processed into small duplex RNA molecules of approximately 21-22 nucleotides (nts) termed small interfering RNAs (siRNAs) by a RNase III enzyme called Dicer. Interaction of siRNAs with a multi-protein complex, termed the RNA-induced silencing complex (RISC), results in sequence specific association of the activated RISC complex with the cognate RNA transcript. This interaction leads to sequence-specific cleavage of the target transcript. Originally discovered in Caenorhabditis elegans, the study of RNAi in mammalian cells has blossomed in the last couple of years with the discovery that introduction of siRNA molecules directly into somatic mammalian cells circumvents the non-specific response vertebrate cells have against larger dsRNA molecules. Emerging as a powerful tool for reverse genetic analysis, RNAi is rapidly being applied to study the function of many genes associated with human disease, in particular those associated with oncogenesis and infectious disease. This review summarizes the mechanism of RNAi and provides an overview of its current applications in medicine.
Mol Genet Metab
PMID:RNA interference and human disease. 1456 61

Double-stranded RNA-mediated interference (RNAi) is a simple and rapid method of silencing gene expression in a range of organisms. The silencing of a gene is a consequence of degradation of RNA into short RNAs that activate ribonucleases to target homologous mRNA. The resulting phenotypes either are identical to those of genetic null mutants or resemble an allelic series of mutants. Specific gene silencing has been shown to be related to two ancient processes, cosuppression in plants and quelling in fungi, and has also been associated with regulatory processes such as transposon silencing, antiviral defense mechanisms, gene regulation, and chromosomal modification. Extensive genetic and biochemical analysis revealed a two-step mechanism of RNAi-induced gene silencing. The first step involves degradation of dsRNA into small interfering RNAs (siRNAs), 21 to 25 nucleotides long, by an RNase III-like activity. In the second step, the siRNAs join an RNase complex, RISC (RNA-induced silencing complex), which acts on the cognate mRNA and degrades it. Several key components such as Dicer, RNA-dependent RNA polymerase, helicases, and dsRNA endonucleases have been identified in different organisms for their roles in RNAi. Some of these components also control the development of many organisms by processing many noncoding RNAs, called micro-RNAs. The biogenesis and function of micro-RNAs resemble RNAi activities to a large extent. Recent studies indicate that in the context of RNAi, the genome also undergoes alterations in the form of DNA methylation, heterochromatin formation, and programmed DNA elimination. As a result of these changes, the silencing effect of gene functions is exercised as tightly as possible. Because of its exquisite specificity and efficiency, RNAi is being considered as an important tool not only for functional genomics, but also for gene-specific therapeutic activities that target the mRNAs of disease-related genes.
Microbiol Mol Biol Rev 2003 Dec
PMID:RNA interference: biology, mechanism, and applications. 1466 79

Although RNA silencing was first discovered in plants, thus far it has been studied biochemically only in animals, where it is known as RNA interference (RNAi). In animals, two components of the RNAi pathway have been identified: Dicer, a multidomain RNase III that converts long double-stranded RNA (dsRNA) into small interfering RNA (siRNA) and the RNA-induced silencing complex (RISC), as siRNA-containing protein-RNA complex that targets complementary mRNA for destruction. We have developed methods for the biochemical dissection of plant RNA silencing. In this chapter, we describe in detail how to use wheat germ extract to study two distinct Dicer-like activities, RNA-dependent RNA polymerase (RdRP), and endogenous microRNA-programmed RISC activities. These comprehensive protocols should prove useful in the further dissection of the plant RNA silencing pathway, as well as for the validation of the predicted targets of endogenous plant microRNAs.
Methods Mol Biol 2004
PMID:Biochemical dissection of RNA silencing in plants. 1477 9

Our understanding of RNA interference has been enhanced by new data concerning RNase III molecules. The role of Dicer has previously been established in RNAi as the originator of 22-mers characteristic of silencing phenomena. Recently, a related RNAse III enzyme, Drosha, has surfaced as another component of the RNAi pathway. In addition to biochemistry, protein structures have proven to be helpful in deciphering the enzymology of RNase III molecules.
Nat Struct Mol Biol 2004 Mar
PMID:RNase III enzymes and the initiation of gene silencing. 1498 73

RNA interference (RNAi) in animals, cosuppression in plants, and quelling in fungi are homology-dependent gene silencing mechanisms in which the introduction of either double-stranded RNA (dsRNA) or transgenes induces sequence-specific mRNA degradation. These phenomena share a common genetic and mechanistic basis. The accumulation of short interfering RNA (siRNA) molecules that guide sequence-specific mRNA degradation is a common feature in both silencing mechanisms, as is the component of the RNase complex involved in mRNA cleavage. During RNAi in animal cells, dsRNA is processed into siRNA by an RNase III enzyme called Dicer. Here we show that elimination of the activity of two Dicer-like genes by mutation in the fungus Neurospora crassa eliminates transgene-induced gene silencing (quelling) and the processing of dsRNA to an siRNA form. The two Dicer-like genes appear redundant because single mutants are quelling proficient. This first demonstration of the involvement of Dicer in gene silencing induced by transgenes supports a model by which a dsRNA produced by the activity of cellular RNA-dependent RNA polymerases on transgenic transcripts is an essential intermediate of silencing.
Mol Cell Biol 2004 Mar
PMID:Redundancy of the two dicer genes in transgene-induced posttranscriptional gene silencing in Neurospora crassa. 1499 90

RNA silencing is a collective term that encompasses the sequence of events that leads to the targeted degradation of cellular mRNA and thus to the silencing of corresponding gene expression. RNA silencing is initiated after introduction into the host genome of a gene that is homologous to an endogenous gene. Transcription of the introduced gene results in the formation of double-stranded RNA (dsRNA) that is cut into smaller dsRNA species termed small interfering RNAs (siRNAs) by an RNaseIII-like enzyme called 'Dicer'. siRNAs associate with a protein complex termed the 'RNA-induced silencing complex' (RISC), which mediates the binding of one strand of siRNAs with mRNAs transcribed from the native 'target' gene. The binding of siRNAs with native gene mRNAs earmarks native gene mRNAs for destruction, resulting in gene silencing. In plants, RNA silencing appears to serve as a defence mechanism against viral pathogens and also to suppress the activity of virus-like mobile genetic elements. In an apparent response to RNA silencing, some plant viruses express suppressors of RNA silencing. RNA silencing also is directly implicated in the regulation of the function(s) of microRNAs, which are the key determinants in an additional cellular mechanism related to the translational repression of genes, the effect of which ultimately impinges on development. The high degree of sequence similarity that exists between genes involved in RNA silencing in widely different organisms underscores the conserved nature of many aspects of the RNA silencing mechanism. However, depending (for example) on the precise nature of the target gene involved, there also are significant differences in the silencing pathways that are engaged by various organisms.
Plant Mol Biol 2004 Jan
PMID:Characteristics of RNA silencing in plants: similarities and differences across kingdoms. 1515 20

An array of gene silencing pathways share a common early step: Dicer cleaves double-stranded RNA (dsRNA) into approximately 20-25 nucleotide fragments that direct the silencing machinery to specific targets. A recent report in Cell reveals how Dicer's two RNase III domains collaborate during dsRNA processing and sets the stage for a deeper understanding of Dicer's roles in later phases of silencing complex assembly.
Mol Cell 2004 Jul 23
PMID:The Making of an siRNA. 1526 Sep 64

In recent years a new mechanism of posttranscriptional gene silencing has been discovered and named RNA interference. The interference is based on mRNA degradation mediated by small double-stranded RNA molecules approximately 21 nucleotides in length, the so-called short interfering or siRNAs. These molecules are produced from long dsRNAs by Dicer, a dsRNA-specific endonuclease, and cause specific degradation of their mRNA-targets by Watson-Crick base-pairing within a 300 kD multi-enzyme complex named RISC. RNAi is highly conserved between plants and animals of various phyla including mammals. The high sequence-specificity of RNAi makes it a new, promising tool in gene-function analysis as well as in potential therapeutics. In this review the discovery and molecular background of RNAi are summarized and possible fields of application pointed out.
Curr Mol Med 2004 Aug
PMID:Silencing of disease-related genes by small interfering RNAs. 1526 22

Introduction of double-stranded RNA into cells causes gene silencing in a sequence-specific manner, involving the coordinated activity of enzymes such as Dicer and RNA-induced silencing complex. Several groups have recently demonstrated that this phenomenon of RNA interference (RNAi) occurs in mammalian cells when small interfering (si)RNAs are used, and have developed vector-based siRNA expression systems that can induce RNAi in living cells. These vector systems use polymerase III promoters, such as U6 or H1, and are classified into two groups based on the form of expressed RNA, tandem or hairpin. This review describes the basis for, and methodology of siRNA expression vectors for mammalian cells.
Curr Opin Mol Ther 2004 Aug
PMID:Vectors for RNA interference. 1546 95

RNA interference (RNAi) is the sequence-specific gene silencing induced by double-stranded RNA. RNAi is mediated by 21-23 nucleotide small interfering RNAs (siRNAs) which are produced from long double-stranded RNAs by RNAse II-like enzyme Dicer. The resulting siRNAs are incorporated into a RNA-induced silencing complex (RISC) that targets and cleaves mRNA complementary to the siRNAs. Since its inception in 1998, RNAi has been demonstrated in organisms ranging from trypanosomes to nematodes to vertebrates. Potential uses already in progress include the examination of specific gene function in living systems, the development of anti-viral and anti-cancer therapies, and genome-wide screens. In this review, we discuss the landmark discoveries that established the contextual framework leading up to our current understanding of RNAi. We also provide an overview of current developments and future applications.
Curr Issues Mol Biol 2005 Jan
PMID:RNA interference: past, present and future. 1558 Jul 76


1 2 3 4 5 6 7 8 9 10 Next >>