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41 - Small silencing non-coding RNAs: cancer connections and significance
- from Part 2.6 - Molecular pathways underlying carcinogenesis: other pathways
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- By Milena S. Nicoloso, RNA Interference and Non-coding RNA Center and the Department of Experimental herapeutics, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA, George A. Calin, RNA Interference and Non-coding RNA Center and the Department of Experimental herapeutics, University of Texas, M.D. Anderson Cancer Center, Houston, TX, USA
- Edited by Edward P. Gelmann, Columbia University, New York, Charles L. Sawyers, Memorial Sloan-Kettering Cancer Center, New York, Frank J. Rauscher, III
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- Book:
- Molecular Oncology
- Published online:
- 05 February 2015
- Print publication:
- 19 December 2013, pp 481-496
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Summary
Focus of the chapter
Despite a few intuitive theories in the sixties that proposed a regulatory role for RNA in controlling gene expression through base-pair complementarity (1,2), the subsequent discovery of transcription factors quenched any further research in this field. As a consequence, for many years RNA has been regarded exclusively as the intermediary molecule between DNA and protein, with the primary role of carrying the genetic information necessary for protein synthesis. Intriguingly, only about 2% of human DNA accounts for protein-coding genes and the total number of proteins does not vary significantly among different species. On the other hand, the extent of non-protein-coding DNA, regarded for a long time as junk DNA, increases proportionally with developmental complexity (3) and over 90% (4) of the genome is actually transcribed in a developmentally regulated manner to produce non-coding RNA (ncRNA) that can be inter-genic, intronic, or overlapping with protein-coding transcripts (5–7). In addition, ncRNAs display precise tissue-expression patterns (8) and are differentially expressed in pathologic conditions such as cancer, and immune or heart diseases (9; for review see 10).
ncRNAs can be conventionally divided into long and small RNAs. Long ncRNAs include those greater than 200 nucleotides (nt) in length that can reach up to 100kb (11,12). Their function and characterization is still underway; however, it is already clear that this heterogeneous class displays important regulatory functions, as shown in developmental processes where they can regulate expression of homeotic genes, oncogenes, and metabolic genes (10). Despite their smaller size, small RNAs are equally important in development, cell biology, and disease, and their discovery triggered the general interest of the scientific community for ncRNAs. Currently, a total of 7053 small RNAs are annotated by Gencode, 85% of which correspond to four major classes: small nuclear (sn)RNAs, small nucleolar (sno)RNAs, miRNAs, and transfer (t)RNAs (13; for small RNA classification and main characteristics, see Table 41.1). In this chapter we will focus mainly on small silencing RNAs that include: microRNAs, which are the most studied class of ncRNAs; piwi-interacting RNAs (piRNAs), which are germline-specific ncRNAs, and finally a brief reference to the most recently identified class of small silencing RNAs, which consists of endogenous small interfering RNAs (endo-siRNAs).
23 - High throughput microRNAs profiling in cancers
- from V - MicroRNAs in disease biology
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- By Muller Fabbri, Center for Human Cancer Genetics The Ohio State University Comprehensive Cancer Center 385L Comprehensive Cancer Center 410 West 10th Avenue Columbus, OH 43210 USA, Ramiro Garzon, Center for Human Cancer Genetics The Ohio State University Comprehensive Cancer Center 385L Comprehensive Cancer Center 410 West 10th Avenue Columbus, OH 43210 USA, Amelia Cimmino, Center for Human Cancer Genetics The Ohio State University Comprehensive Cancer Center 385L Comprehensive Cancer Center 410 West 10th Avenue Columbus, OH 43210 USA, George Adrian Calin, Center for Human Cancer Genetics The Ohio State University Comprehensive Cancer Center 385L Comprehensive Cancer Center 410 West 10th Avenue Columbus, OH 43210 USA, Carlo Maria Croce, Center for Human Cancer Genetics The Ohio State University Comprehensive Cancer Center 385L Comprehensive Cancer Center 410 West 10th Avenue Columbus, OH 43210 USA
- Edited by Krishnarao Appasani
- Foreword by Sidney Altman, Victor R. Ambros
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- Book:
- MicroRNAs
- Published online:
- 22 August 2009
- Print publication:
- 20 December 2007, pp 309-321
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Summary
Introduction
MicroRNAs are small noncoding RNAgenes (18–24 nucleotides in length) that have been identified in different organisms from the nematode C. elegans to humans (for reviews see Bartel, 2004; He and Hannon, 2004). Recently it has become more and more evident that microRNAs play important roles in regulating the translation and degradation of mRNAs through base pairing to perfectly (in plants) or partially (in mammals) complementary sites, mainly but not exclusively in the untranslated region (UTR) of the target mRNA (Lagos-Quintana et al., 2001; Lau et al., 2001; Lee and Ambros, 2001). MicroRNAs are initially transcribed by RNA polymerase II (pol II) as long primary transcripts called primary-miRNAs (pri-miRNAs). A double-stranded RNA-specific ribonuclease called Drosha is responsible for the processing of pri-miRNAs into hairpin RNAs of 70–100bp known as pre-miRNAs, which contain a two nucleotide 3′ overhang characteristic of RNase III cleavage products (Cullen, 2004). Pre-miRNAs are transported to the cytoplasm by the nuclear export factor exportin 5. Once in the cytoplasm pre-miRNAs are processed by a second, double-stranded specific ribonuclease III called Dicer in a 18–24 nucleotide duplex. The product of Dicer's cleavage is incorporated into a large protein complex called RISC (RNA-induced silencing complex), which includes as core components the Argonaute proteins (Ago1–4 in humans). One strand of the miRNA duplex remains stably associated with RISC and becomes the mature miRNA. The opposite strand, called passenger strand or miRNA, is discarded through two different mechanisms.