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http://dx.doi.org/10.4014/jmb.1304.04057

Metabolomic Response of Chlamydomonas reinhardtii to the Inhibition of Target of Rapamycin (TOR) by Rapamycin  

Lee, Do Yup (Department of Advanced Fermentation Fusion Science and Technology, Kookmin University)
Fiehn, Oliver (Genome Center, University of California)
Publication Information
Journal of Microbiology and Biotechnology / v.23, no.7, 2013 , pp. 923-931 More about this Journal
Abstract
Rapamycin, known as an inhibitor of Target of Rapamycin (TOR), is an immunosuppressant drug used to prevent rejection in organ transplantation. Despite the close association of the TOR signaling cascade with various scopes of metabolism, it has not yet been thoroughly investigated at the metabolome level. In our current study, we applied mass spectrometric analysis for profiling primary metabolism in order to capture the responsive dynamics of the Chlamydomonas metabolome to the inhibition of TOR by rapamycin. Accordingly, we identified the impact of the rapamycin treatment at the level of metabolomic phenotypes that were clearly distinguished by multivariate statistical analysis. Pathway analysis pinpointed that inactivation of the TCA cycle was accompanied by the inhibition of cellular growth. Relative to the constant suppression of the TCA cycle, most amino acids were significantly increased in a time-dependent manner by longer exposure to rapamycin treatment, after an initial down-regulation at the early stage of exposure. Finally, we explored the isolation of the responsive metabolic factors into the rapamycin treatment and the culture duration, respectively.
Keywords
Metabolomics; mass spectrometry; Chlamydomonas reinhardtii; target of rapamycin;
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1 Wullschleger S, Loewith R, Hall MN. 2006. TOR signaling in growth and metabolism. Cell 124: 471-484.   DOI   ScienceOn
2 Xia J, Mandal R, Sinelnikov IV, Broadhurst D, Wishart DS. 2012. MetaboAnalyst 2.0 - a comprehensive server for metabolomic data analysis. Nucleic Acids Res. 40: W127-W133.   DOI
3 Kofman AE, McGraw MR, Payne CJ. 2012. Rapamycin increases oxidative stress response gene expression in adult stem cells. Aging (Albany NY) 4: 279.
4 Lee D, Park J, Barupal D, Fiehn O. 2012. System response of metabolic networks in Chlamydomonas reinhardtii to total available ammonium. Mol. Cell. Proteomics 11: 973-988.   DOI
5 Lee DY, Fiehn O. 2008. High quality metabolomic data for Chlamydomonas reinhardtii. Plant Methods 4: 7.   DOI   ScienceOn
6 Luo F, Khan L, Bastani F, Yen I-L, Zhou J. 2004. A dynamically growing self-organizing tree (DGSOT) for hierarchical clustering gene expression profiles. Bioinformatics 20: 2605-2617.   DOI   ScienceOn
7 Messac A, Ismail-Yahaya A, Mattson CA. 2003. The normalized normal constraint method for generating the Pareto frontier. Struct. Multidiscip. Opt. 25: 86-98.   DOI
8 Mahfouz MM, Kim S, Delauney AJ, Verma DPS. 2006. Arabidopsis target of rapamycin interacts with raptor, which regulates the activity of S6 kinase in response to osmotic stress signals. Plant Cell 18: 477-490.   DOI   ScienceOn
9 Marobbio CM, Pisano I, Porcelli V, Lasorsa FM, Palmieri L. 2012. Rapamycin reduces oxidative stress in frataxin-deficient yeast cells. Mitochondrion 12: 156-161.   DOI   ScienceOn
10 Menand B, Desnos T, Nussaume L, Berger F, Bouchez D, Meyer C, et al. 2002. Expression and disruption of the Arabidopsis TOR (target of rapamycin) gene. Proc. Natl. Acad. Sci. USA 99: 6422-6427.   DOI   ScienceOn
11 Perez-Perez ME, Florencio FJ, Crespo JL. 2010. Inhibition of target of rapamycin signaling and stress activate autophagy in Chlamydomonas reinhardtii. Plant Physiol. 152: 1874-1888.   DOI   ScienceOn
12 Qualley AV, Widhalm JR, Adebesin F, Kish CM, Dudareva N. 2012. Completion of the core ${\beta}$-oxidative pathway of benzoic acid biosynthesis in plants. Proc. Natl. Acad. Sci. USA 109: 16383-16388.   DOI
13 Saunders RN, Metcalfe MS, Nicholson ML. 2001. Rapamycin in transplantation: A review of the evidence. Kidney Int. 59: 3-16.   DOI   ScienceOn
14 Barbet N, Schneider U, Helliwell S, Stansfield I, Tuite M, Hall M. 1996. TOR controls translation initiation and early G1 progression in yeast. Molec. Biol. Cell 7: 25.   DOI   ScienceOn
15 Crespo JL, Diaz-Troya S, Florencio FJ. 2005. Inhibition of target of rapamycin signaling by rapamycin in the unicellular green alga Chlamydomonas reinhardtii. Plant Physiol. 139: 1736-1749.   DOI   ScienceOn
16 Benkeblia N, Shinano T, Osaki M. 2007. Metabolite profiling and assessment of metabolome compartmentation of soybean leaves using non-aqueous fractionation and GC-MS analysis. Metabolomics 3: 297-305.   DOI
17 Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, et al. 1994. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369: 756-758.   DOI   ScienceOn
18 Caldana C, Li Y, Leisse A, Zhang Y, Bartholomaeus L, Fernie AR, et al. 2013. Systemic analysis of inducible target of rapamycin mutants reveal a general metabolic switch controlling growth in Arabidopsis thaliana. Plant J. 73: 897-909.   DOI   ScienceOn
19 Diaz-Troya S, Florencio FJ, Crespo JL. 2008. Target of rapamycin and LST8 proteins associate with membranes from the endoplasmic reticulum in the unicellular green alga Chlamydomonas reinhardtii. Eukaryotic Cell 7: 212-222.   DOI   ScienceOn
20 Eisen MB, Spellman PT, Brown PO, Botstein D. 1998. Cluster analysis and display of genome-wide expression patterns. Proc. Natl. Acad. Sci. USA 95: 14863-14868.   DOI   ScienceOn
21 Fiehn O, Kopka J, Dormann P, Altmann T, Trethewey RN, Willmitzer L. 2000. Metabolite profiling for plant functional genomics. Nature Biotechnol. 18: 1157-1161.   DOI   ScienceOn
22 Harris EH, Stern DB, Witman G. 1989. The Chlamydomonas Sourcebook. Cambridge University Press, UK.
23 Goodacre R, Vaidyanathan S, Dunn WB, Harrigan GG, Kell DB. 2004. Metabolomics by numbers: Acquiring and understanding global metabolite data. Trends Biotechnol. 22: 245-252.   DOI   ScienceOn
24 Heitman J, Movva NR, Hall MN. 1991. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253: 905-909.   DOI
25 Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, et al. 2002. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: Involvement of vascular endothelial growth factor. Nature Med. 8: 128-135.   DOI   ScienceOn
26 He Z, Li L, Luan S. 2004. Immunophilins and parvulins. Superfamily of peptidyl prolyl isomerases in Arabidopsis. Plant Physiol. 134: 1248-1267.   DOI   ScienceOn
27 Hutschenreuther A, Kiontke A, Birkenmeier G, Birkemeyer C. 2012. Comparison of extraction conditions and normalization approaches for cellular metabolomics of adherent growing cells with GC-MS. Anal. Methods 4: 1953-1963.   DOI
28 Kind T, Wohlgemuth G, Lee DY, Lu Y, Palazoglu M, Shahbaz S, et al. 2009. FiehnLib: Mass spectral and retention index libraries for metabolomics based on quadrupole and time-of-flight gas chromatography/mass spectrometry. Anal. Chem. 81: 10038-10048.   DOI   ScienceOn
29 Saxena D, Kannan K, Brandriss MC. 2003. Rapamycin treatment results in GATA factor-independent hyperphosphorylation of the proline utilization pathway activator in Saccharomyces cerevisiae. Eukaryotic Cell 2: 552-559.   DOI
30 Vezina C, Kudelski A, Sehgal S. 1975. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiotics 28: 721.   DOI
31 Sengupta A, Ghosh M. 2012. Comparison of native and capric acid-enriched mustard oil effects on oxidative stress and antioxidant protection in rats. Br. J. Nutr. 107: 845.   DOI   ScienceOn
32 Sturn A, Quackenbush J, Trajanoski Z. 2002. Genesis: Cluster analysis of microarray data. Bioinformatics 18: 207-208.   DOI   ScienceOn
33 Toronen P, Kolehmainen M, Wong G, Castren E. 1999. Analysis of gene expression data using self-organizing maps. FEBS Lett. 451: 142-146.   DOI   ScienceOn
34 Tataranni T, Biondi G, Cariello M, Mangino M, Colucci G, Rutigliano M, et al. 2011. Rapamycin-induced hypophosphatemia and insulin resistance are associated with mTORC2 activation and klotho expression. Am. J. Transplant. 11: 1656-1664.   DOI