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      Development of a Whole Organism Platform for Phenotype-Based Analysis of IGF1R-PI3K-Akt-Tor Action

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          Abstract

          Aberrant regulation of the insulin-like growth factor (IGF)/insulin (IIS)-PI3K-AKT-TOR signaling pathway is linked to major human diseases, and key components of this pathway are targets for therapeutic intervention. Current assays are molecular target- or cell culture-based platforms. Due to the great in vivo complexities inherited in this pathway, there is an unmet need for whole organism based assays. Here we report the development of a zebrafish transgenic line, Tg( igfbp5a: GFP), which faithfully reports the mitotic action of IGF1R-PI3K-Akt-Tor signaling in epithelial cells in real-time. This platform is well suited for high-throughput assays and real-time cell cycle analysis. Using this platform, the dynamics of epithelial cell proliferation in response to low [Ca 2+] stress and the distinct roles of Torc1 and Torc2 were elucidated. The availability of Tg( igfbp5a: GFP) line provides a whole organism platform for phenotype-based discovery of novel players and inhibitors in the IIS-PI3K-Akt-Tor signaling pathway.

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          Amino acid signalling upstream of mTOR.

          Jenna L. Jewell, Ryan C Russell, Kun-Liang Guan (2013)
          Mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that is part of mTOR complex 1 (mTORC1), a master regulator that couples amino acid availability to cell growth and autophagy. Multiple cues modulate mTORC1 activity, such as growth factors, stress, energy status and amino acids. Although amino acids are key environmental stimuli, exactly how they are sensed and how they activate mTORC1 is not fully understood. Recently, a model has emerged whereby mTORC1 activation occurs at the lysosome and is mediated through an amino acid sensing cascade involving RAG GTPases, Ragulator and vacuolar H(+)-ATPase (v-ATPase).
          Article 0 comments Cited 330 times – based on 0 reviews     Review now
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            AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1.

            R Medema, G. J. P. L. Kops, J Bos … (2000)
            The Forkhead transcription factors AFX, FKHR and FKHR-L1 are orthologues of DAF-16, a Forkhead factor that regulates longevity in Caenorhabditis elegans. Here we show that overexpression of these Forkhead transcription factors causes growth suppression in a variety of cell lines, including a Ras-transformed cell line and a cell line lacking the tumour suppressor PTEN. Expression of AFX blocks cell-cycle progression at phase G1, independent of functional retinoblastoma protein (pRb) but dependent on the cell-cycle inhibitor p27kip1. Indeed, AFX transcriptionally activates p27kip1, resulting in increased protein levels. We conclude that AFX-like proteins are involved in cell-cycle regulation and that inactivation of these proteins is an important step in oncogenic transformation.
            Article 0 comments Cited 239 times – based on 0 reviews     Review now
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              Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes.

              Tian-Tian Wang, Luz Elisa Tavera-Mendoza, David Laperrière … (2005)
              1alpha,25-Dihydroxyvitamin D3 [1,25(OH)2D3] regulates calcium homeostasis and controls cellular differentiation and proliferation. The vitamin D receptor (VDR) is a ligand-regulated transcription factor that recognizes cognate vitamin D response elements (VDREs) formed by direct or everted repeats of PuG(G/T)TCA motifs separated by 3 or 6 bp (DR3 or ER6). Here, we have identified direct 1,25(OH)2D3 target genes by combining 35,000+ gene microarrays and genome-wide screens for consensus DR3 and ER6 elements, and DR3 elements containing single nucleotide substitutions. We find that the effect of a nucleotide substitution on VDR binding in vitro does not predict VDRE function in vivo, because substitutions that disrupted binding in vitro were found in several functional elements. Hu133A microarray analyses, performed with RNA from human SCC25 cells treated with 1,25(OH)2D3 and protein synthesis inhibitor cycloheximide, identified more than 900 regulated genes. VDREs lying within -10 to +5 kb of 5'-ends were assigned to 65% of these genes, and VDR binding was confirmed to several elements in vivo. A screen of the mouse genome identified more than 3000 conserved VDREs, and 158 human genes containing conserved elements were 1,25(OH2)D3-regulated on Hu133A microarrays. These experiments also revealed 16 VDREs in 11 of 12 genes induced more than 10-fold in our previous microarray study, five elements in the human gene encoding the epithelial calcium channel TRPV6, as well as novel 1,25(OH2)D3 target genes implicated in regulation of cell cycle progression. The combined approaches used here thus provide numerous insights into the direct target genes underlying the broad physiological actions of 1,25(OH)2D3.
              Article 0 comments Cited 167 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Cunming Duan: cduan@umich.edu
                Journal
                Journal ID (nlm-ta): Sci Rep
                Journal ID (iso-abbrev): Sci Rep
                Title: Scientific Reports
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2045-2322
                Publication date (Electronic): 17 May 2017
                Publication date PMC-release: 17 May 2017
                Publication date Collection: 2017
                Volume: 7
                Electronic Location Identifier: 1994
                Affiliations
                [1 ]ISNI 0000 0001 2152 3263, GRID grid.4422.0, The Key Laboratory of Mariculture, Education Ministry of China and College of Fisheries, , Ocean University of China, ; Qingdao, 266003 China
                [2 ]ISNI 0000000086837370, GRID grid.214458.e, Department of Molecular, Cellular and Developmental Biology, , University of Michigan, ; Ann Arbor, MI 48109 USA
                [3 ]GRID grid.443668.b, National Engineering Research Center for Marine Facilities Aquaculture, , School of Marine Science and Technology, Zhejiang Ocean University, ; Zhoushan, 316022 China
                [4 ]ISNI 0000 0004 1936 9676, GRID grid.133342.4, Department of Molecular, Cellular and Developmental Biology, , University of California, ; Santa Barbara, CA 93106 USA
                Article
                Publisher ID: 1687
                DOI: 10.1038/s41598-017-01687-3
                PMC ID: 5435685
                PubMed ID: 28515443
                SO-VID: 4951e1b4-e2f1-4ac3-95cc-60748b518c26
                Copyright © © The Author(s) 2017
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 24 November 2016
                Date accepted : 3 April 2017
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Uncategorized
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