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      miR-17–92 cluster: ups and downs in cancer and aging

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      Author(s): , ,
      Publication date (Electronic):
      Journal: Biogerontology
      Publisher: Springer Netherlands
      Keywords: miRNA, miR-17–92, Aging, TOR, PTEN, miR-19

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          Abstract

          The miR-17–92 cluster encoding 6 single mature miRNAs was identified a couple of years ago to contain the first oncogenic miRNAs. Now, one of these 6 miRNAs, miR-19 has been identified as the key responsible for this oncogenic activity. This in turn reduces PTEN levels and in consequence activates the AKT/mTOR pathway that is also prominently involved in modulation of organismal life spans. In contrast, miR-19 and other members of the miR-17–92 cluster are found to be commonly downregulated in several human replicative and organismal aging models. Taken together, these findings suggest that miR-19 and the other members of the miR-17–92 cluster might be important regulators on the cross-roads between aging and cancer. Therefore, we here briefly summarize how this cluster is transcriptionally regulated, which target mRNAs have been confirmed so far and how this might be linked to modulation of organismal life-spans.

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          Prediction of mammalian microRNA targets.

          Benjamin Lewis, I-hung Shih, Matthew W Jones-Rhoades … (2003)
          MicroRNAs (miRNAs) can play important gene regulatory roles in nematodes, insects, and plants by basepairing to mRNAs to specify posttranscriptional repression of these messages. However, the mRNAs regulated by vertebrate miRNAs are all unknown. Here we predict more than 400 regulatory target genes for the conserved vertebrate miRNAs by identifying mRNAs with conserved pairing to the 5' region of the miRNA and evaluating the number and quality of these complementary sites. Rigorous tests using shuffled miRNA controls supported a majority of these predictions, with the fraction of false positives estimated at 31% for targets identified in human, mouse, and rat and 22% for targets identified in pufferfish as well as mammals. Eleven predicted targets (out of 15 tested) were supported experimentally using a HeLa cell reporter system. The predicted regulatory targets of mammalian miRNAs were enriched for genes involved in transcriptional regulation but also encompassed an unexpectedly broad range of other functions.
          Article 0 comments Cited 1051 times – based on 0 reviews     Review now
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            Chemokine signaling via the CXCR2 receptor reinforces senescence.

            Juan C. Acosta, Ana O'Loghlen, Ana Banito … (2008)
            Cells enter senescence, a state of stable proliferative arrest, in response to a variety of cellular stresses, including telomere erosion, DNA damage, and oncogenic signaling, which acts as a barrier against malignant transformation in vivo. To identify genes controlling senescence, we conducted an unbiased screen for small hairpin RNAs that extend the life span of primary human fibroblasts. Here, we report that knocking down the chemokine receptor CXCR2 (IL8RB) alleviates both replicative and oncogene-induced senescence (OIS) and diminishes the DNA-damage response. Conversely, ectopic expression of CXCR2 results in premature senescence via a p53-dependent mechanism. Cells undergoing OIS secrete multiple CXCR2-binding chemokines in a program that is regulated by the NF-kappaB and C/EBPbeta transcription factors and coordinately induce CXCR2 expression. CXCR2 upregulation is also observed in preneoplastic lesions in vivo. These results suggest that senescent cells activate a self-amplifying secretory network in which CXCR2-binding chemokines reinforce growth arrest.
            Article 0 comments Cited 624 times – based on 0 reviews     Review now
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              Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway.

              Pankaj Kapahi, Brian M. Zid, Tony Harper … (2004)
              In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.
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                Author and article information

                Contributors
                : +43-1-47654 6230 , +43-1-3697615 , johannes.grillari@boku.ac.at
                Journal
                Journal ID (nlm-ta): Biogerontology
                Title: Biogerontology
                Publisher: Springer Netherlands (Dordrecht )
                ISSN (Print): 1389-5729
                ISSN (Electronic): 1573-6768
                Publication date (Electronic): 1 May 2010
                Publication date PMC-release: 1 May 2010
                Publication date (Print): August 2010
                Volume: 11
                Issue: 4
                Pages: 501-506
                Affiliations
                Aging and Immortalization Research, Department of Biotechnology, University of Natural Resources and Applied Life Sciences Vienna, Muthgasse 18, 1190 Vienna, Austria
                Article
                Publisher ID: 9272
                DOI: 10.1007/s10522-010-9272-9
                PMC ID: 2899009
                PubMed ID: 20437201
                SO-VID: 594510e1-efcc-4bf4-b774-1c30dd2c986b
                Copyright © © The Author(s) 2010
                History
                Date received : 22 March 2010
                Date accepted : 6 April 2010
                Categories
                Subject: Opinion
                Custom metadata
                issue-copyright-statement © Springer Science+Business Media B.V. 2010

                ScienceOpen disciplines: Geriatric medicine
                Keywords: pten,aging,tor,mir-19,mir-17–92,mirna
                Data availability:
                ScienceOpen disciplines: Geriatric medicine
                Keywords: pten, aging, tor, mir-19, mir-17–92, mirna

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