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      A pathophysiological view of the long non-coding RNA world

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          Abstract

          Because cells are constantly exposed to micro-environmental changes, they require the ability to adapt to maintain a dynamic equilibrium. Proteins are considered critical for the regulation of gene expression, which is a fundamental process in determining the cellular responses to stimuli. Recently, revolutionary findings in RNA research and the advent of high-throughput genomic technologies have revealed a pervasive transcription of the human genome, which generates many long non-coding RNAs (lncRNAs) whose roles are largely undefined. However, there is evidence that lncRNAs are involved in several cellular physiological processes such as adaptation to stresses, cell differentiation, maintenance of pluripotency and apoptosis. The correct balance of lncRNA levels is crucial for the maintenance of cellular equilibrium, and the dysregulation of lncRNA expression is linked to many disorders; certain transcripts are useful prognostic markers for some of these pathologies. This review revisits the classic concept of cellular homeostasis from the perspective of lncRNAs specifically to understand how this novel class of molecules contributes to cellular balance and how its dysregulated expression can lead to the onset of pathologies such as cancer.

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          Most cited references109

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          The transcriptional landscape of the mammalian genome.

          This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5' and 3' boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
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            RNA maps reveal new RNA classes and a possible function for pervasive transcription.

            Significant fractions of eukaryotic genomes give rise to RNA, much of which is unannotated and has reduced protein-coding potential. The genomic origins and the associations of human nuclear and cytosolic polyadenylated RNAs longer than 200 nucleotides (nt) and whole-cell RNAs less than 200 nt were investigated in this genome-wide study. Subcellular addresses for nucleotides present in detected RNAs were assigned, and their potential processing into short RNAs was investigated. Taken together, these observations suggest a novel role for some unannotated RNAs as primary transcripts for the production of short RNAs. Three potentially functional classes of RNAs have been identified, two of which are syntenically conserved and correlate with the expression state of protein-coding genes. These data support a highly interleaved organization of the human transcriptome.
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              A coding-independent function of gene and pseudogene mRNAs regulates tumour biology

              The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis. However, given that microRNAs bind to RNAs, we hypothesized that RNAs possess a biological role in cancer cells that relies upon their ability to compete for microRNA binding and is independent of their protein-coding function. As a paradigm for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene (PTENP1) and the critical consequences of this interaction. We find that PTENP1 is biologically active as determined by its ability to regulate cellular levels of PTEN, and that it can exert a growth-suppressive role. We also show that PTENP1 locus is selectively lost in human cancer. We extend our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS. Further, we demonstrate that the transcripts of protein coding genes such as PTEN are also biologically active. Together, these findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                November 2014
                15 November 2014
                : 5
                : 22
                : 10976-10996
                Affiliations
                1 Department of Experimental and Clinical Biomedical Sciences, University of Florence, Italy
                Author notes
                Correspondence to: Federico Di Gesualdo, federicodigesualdo@ 123456yahoo.it
                Article
                10.18632/oncotarget.2770
                4294373
                25428918
                714d7a3a-78b6-47bb-9732-44b557418e50
                Copyright: © 2014 Di Gesualdo et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 16 September 2014
                : 14 November 2014
                Categories
                Review

                Oncology & Radiotherapy
                cellular homeostasis,lncrna dysregulation,cancer hallmarks
                Oncology & Radiotherapy
                cellular homeostasis, lncrna dysregulation, cancer hallmarks

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