miRNA
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In 1993, Science magazine named p53 the "Molecule of the Year" based upon the significance of this tumor suppressor gene as a critical part of a signal transduction pathway, helping cells respond to DNA damage. With respect to the functional significance, p53 has a number of anti-cancer mechanisms including activation of DNA repair following sustained damage, arresting cell cycle processes following damage, and initiating apoptosis if damage is beyond repair. Interestingly, in normal, undamaged cells, p53 exists in an inactive form, bound to the protein MDM2, until DNA damage occurs and MDM2 is released through phosphorylation. Developing technology has enabled researchers to look at the role of p53 in evoking a broad spectrum of cellular responses to damage, particularly in cancerous cells. MicroRNAs have been implicated as having regulatory involvement in a multitude of biological pathways, and the p53 signal transduction pathway is no different. Traditionally, miRNA expression has been tested using low-throughput techniques such as Northern-blot analysis and real-time PCR, but new developments in microarray technology now enable global profiling of all miRNA genes and their precursors in any sample type.
Cristina Méndez Vidal and colleagues at the Karolinska Institute in Sweden (2006) studied the p53-induced Wig-1 protein in mouse, characterizing the binding of double-stranded RNAs that have structural characteristics similar to siRNAs and miRNAs. The group used cell culture, transformation, and immunological techniques to characterize the binding of Wig-1 to siRNAs/miRNAs in vitro, raising the possibility that Wig-1 is involved in miRNA-mediated regulation of cell growth and survival and acts to promote p53-induced cell growth arrest and/or apoptosis. The group suggests that Wig-1 binding to specific miRNAs could increase the stability of the imperfect small duplex regions formed by the miRNA and its mRNA targets, potentially affecting mRNA stability, transport, and/or translation. Based on their findings, the researchers suggest that further functional studies of Wig-1 mutants lacking dsRNA binding activity will ultimately clarify the role of Wig-1 dsRNA binding in the p53 tumor suppressor pathway.
Title: MicroRNAs and messenger RNA turnover.
Authors: Chekanova JA, Belostotsky DA
Journal: Methods Mol Biol. 2006;342:73-85.
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An international collaboration between researchers in Netherlands, Italy and Japan (2006) performed genetic screens for novel functions of miRNAs by developing a library of vectors expressing the majority of cloned human miRNAs and corresponding DNA barcode arrays. In a screen for miRNAs that cooperate with oncogenes in cellular transformation, the group identified miR-372 and miR-373, each permitting proliferation and tumorigenesis of primary human cells that harbor both oncogenic RAS and active wild-type p53. These miRNAs were found to neutralize p53-mediated CDK inhibition, possibly through direct inhibition of the expression of the tumor-suppressor LATS2. The research of this team provides evidence that these miRNAs are potential novel oncogenes participating in the development of human testicular germ cell tumors by numbing the p53 pathway, thus allowing tumorigenic growth in the presence of wild-type p53.
Title: A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors.
Authors: Voorhoeve PM, le Sage C, Schrier M, Gillis AJ, Stoop H, Nagel R, Liu YP, van Duijse J, Drost J, Griekspoor A, Zlotorynski E, Yabuta N, De Vita G, Nojima H, Looijenga LH, Agami R
Journal: Cell, Vol 124, Issue 6: 1169-81
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Michael Dews et al (2006) examined augmentation of tumor angiogenesis by a Myc-activated microRNA cluster to address the role of Myc in neovascularization of genetically complex tumors. The team used p53-null mouse colonocytes, which can be transformed in vitro by low-grade overexpression of either activated K-Ras or Myc, to characterize growth properties of RasGfp versus RasGfpMyc p53-null colonocytes in vivo and in vitro. To determine the contribution of Myc to neoplastic growth, the researchers performed histological examination of size-matched tumors and then followed this analysis with microarray data to determine the effects of Myc on expression of other pro- and anti-angiogenic molecules (validated by real-time quantitative RT-PCR and immunoblotting). These analyses were followed by protein expression and cell growth studies to determine the effects of miR-17-92 upregulation in Ras-only cells on neoplastic growth. The results of this study demonstrate that miR-17-92 affects non–cell-autonomous processes such as tumor neovascularization. Thus, antisense-based microRNA targeting, an emerging therapeutic technology might be effective even against apoptosis-resistant tumors.
Title: Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster.
Authors: Dews M, Homayouni A, Yu D, Murphy D, Sevignani C, Wentzel E, Furth EE, Lee WM, Enders GH, Mendell JT, Thomas-Tikhonenko A
Journal: Nat Genet, Vol 38, Issue 9: 1060-5
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Title: Probing tumor phenotypes using stable and regulated synthetic microRNA precursors.
Authors: Dickins RA, Hemann MT, Zilfou JT, Simpson DR, Ibarra I, Hannon GJ, Lowe SW
Journal: Nat Genet, Vol 37, Issue 11: 1289-95
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Title: Molecular profiling of cervical neoplasia.
Authors: Martin CM, Astbury K, O'Leary JJ
Journal: Expert Rev Mol Diagn, Vol 6, Issue 2: 217-29
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Title: Differentially regulated micro-RNAs and actively translated messenger RNA transcripts by tumor suppressor p53 in colon cancer.
Authors: Xi Y, Shalgi R, Fodstad O, Pilpel Y, Ju J
Journal: Clin Cancer Res, Vol 12, Issue 7 Pt 1: 2014-24
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Title: A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes.
Authors: Kent OA, Mendell JT
Journal: Oncogene, Vol 25, Issue 46: 6188-96
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