Article

Small regulatory RNAs in mammals

Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia
Human Molecular Genetics (Impact Factor: 6.39). 05/2005; 14 Spec No 1(Spec No 1):R121-32. DOI: 10.1093/hmg/ddi101
Source: PubMed

ABSTRACT

Mammalian cells harbor numerous small non-protein-coding RNAs, including small nucleolar RNAs (snoRNAs), microRNAs (miRNAs), short interfering RNAs (siRNAs) and small double-stranded RNAs, which regulate gene expression at many levels including chromatin architecture, RNA editing, RNA stability, translation, and quite possibly transcription and splicing. These RNAs are processed by multistep pathways from the introns and exons of longer primary transcripts, including protein-coding transcripts. Most show distinctive temporal- and tissue-specific expression patterns in different tissues, including embryonal stem cells and the brain, and some are imprinted. Small RNAs control a wide range of developmental and physiological pathways in animals, including hematopoietic differentiation, adipocyte differentiation and insulin secretion in mammals, and have been shown to be perturbed in cancer and other diseases. The extent of transcription of non-coding sequences and the abundance of small RNAs suggests the existence of an extensive regulatory network on the basis of RNA signaling which may underpin the development and much of the phenotypic variation in mammals and other complex organisms and which may have different genetic signatures from sequences encoding proteins.

Download full-text

Full-text

Available from: John S Mattick, Jun 13, 2015
  • Source
    • "However, it remains to be clarified whether these effects are due to inhibition of EGFR kinase activity. MicroRNAs (miRNAs) are involved in processes of carcinogenic including development, differentiation, proliferation, and apoptosis404142. Aberrant expression and function of microRNAs have been associated with tumorigenesis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor (TKI), has been approved for HER2-positive breast cancer patients. Nevertheless, its inhibitory effect on EGFR did not deliver clinical benefits for triple-negative breast cancer (TNBC) patients even EGFR overexpression was frequently found in this disease. Moreover, lapatinib was unexpectedly found to enhance metastasis of TNBC cells, but the underlying mechanisms are not fully understood. In this study, we explored that the level of interleukin-6 (IL-6) was elevated in lapatinib-treated TNBC cells. Treatment with IL-6 antibody abolished the lapatinib-induced migration. Mechanistically, the signaling axis of Raf-1/mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinases (JNKs), p38 MAPK, and activator protein 1 (AP-1) was activated in response to lapatinib treatment to induce IL-6 expression. Furthermore, our data showed that microRNA-7 directly binds and inhibits Raf-1 3'UTR activity, and that down-regulation of miR-7 by lapatinib contributes to the activation of Raf-1 signaling pathway and the induction of IL-6 expression. Our results not only revealed IL-6 as a key regulator of lapatinib-induced metastasis, but also explored the requirement of miR7/Raf-1/MAPK/AP-1 axis in lapatinib-induced IL-6 expression.
    Preview · Article · Oct 2015 · Oncotarget
  • Source
    • "Nowadays, it is assumed that 98% of the transcribed RNA in humans is not translated into a protein (Mattick & Makunin, 2005). Previously considered to be simply transcriptional junk, these untranslated RNAs (noncoding RNAs, ncRNAs) can have catalytic activity, serve as protein scaffolds, guide the cellular machinery, and are crucial in all aspects of gene expression, such as regulating chromatin remodeling, transcription, and many posttranscriptional events, both in prokaryotes and eukaryotes (Baker, 2011; Guttman & Rinn, 2012; Mattick et al., 2005; Morris & Mattick, 2014; Ponting, Oliver, & Reik, 2009; Storz, Altuvia, & Wassarman, 2005; Wiedenheft, Sternberg, & Doudna, 2012). Some ncRNAs have 100,000 nucleotides such as the long ncRNA Air present in mammals, whereas silencing RNAs may be only 20 nucleotides long (Storz et al., 2005) and are considered as a potential new class of drugs (Fichou & Férec, 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Although functional significance of large noncoding RNAs and their complexes with proteins is well recognized, structural information for this class of systems is very scarce. Their inherent flexibility causes problems in crystallographic approaches, while their typical size is beyond the limits of state-of-the-art purely NMR-based approaches. Here, we review an approach that combines high-resolution NMR restraints with lower resolution long-range constraints based on site-directed spin labeling and measurements of distance distribution restraints in the range between 15 and 80Å by the four-pulse double electron-electron resonance (DEER) EPR technique. We discuss sample preparation, the basic assumptions behind data analysis in the EPR-based distance measurements, treatment of the label-based constraints in generation of the structure, and the back-calculation of distance distributions for structure validation. Step-by-step protocols are provided for DEER distance distribution measurements including data analysis and for CYANA based structure calculation using combined NMR and EPR data. © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Jun 2015 · Methods in enzymology
  • Source
    • "Recently, emerging evidence has pointed to an important role of RNAs, particularly non-protein coding RNAs (ncRNA) in controlling multiple epigenetic phenomena such as X-chromosome inactivation, gene imprinting and RNAi-mediated silencing (Bernstein and Allis, 2005; Mattick and Makunin, 2006). The sizes of ncRNAs range from 21 nucleotides (nt), as in the case of mature microRNAs (miRNAs), to more than 100,000 nt, such as the Air (antisense to Igf2r) RNA (Lyle et al., 2000; Storz, 2002; Bartel, 2004; Mattick and Makunin, 2005; Cao et al., 2006). Several distinct classes of ncRNAs, such as small nucleolar RNA (snoRNA), microRNA (miRNA) and long ncRNA (lncRNA), have been found highly expressed in the nervous system (Cao et al., 2006; Mehler and Mattick, 2006, 2007; Mehler, 2008). "

    Full-text · Dataset · Jun 2015
Show more