title: Growth control of the eukaryote cell: a systems biology study in yeast.
abstract: BACKGROUND
  Cell growth underlies many key cellular and developmental processes, yet a limited number of studies have been carried out on cell-growth regulation. Comprehensive studies at the transcriptional, proteomic and metabolic levels under defined controlled conditions are currently lacking.
  
  
  RESULTS
  Metabolic control analysis is being exploited in a systems biology study of the eukaryotic cell. Using chemostat culture, we have measured the impact of changes in flux (growth rate) on the transcriptome, proteome, endometabolome and exometabolome of the yeast Saccharomyces cerevisiae. Each functional genomic level shows clear growth-rate-associated trends and discriminates between carbon-sufficient and carbon-limited conditions. Genes consistently and significantly upregulated with increasing growth rate are frequently essential and encode evolutionarily conserved proteins of known function that participate in many protein-protein interactions. In contrast, more unknown, and fewer essential, genes are downregulated with increasing growth rate; their protein products rarely interact with one another. A large proportion of yeast genes under positive growth-rate control share orthologs with other eukaryotes, including humans. Significantly, transcription of genes encoding components of the TOR complex (a major controller of eukaryotic cell growth) is not subject to growth-rate regulation. Moreover, integrative studies reveal the extent and importance of post-transcriptional control, patterns of control of metabolic fluxes at the level of enzyme synthesis, and the relevance of specific enzymatic reactions in the control of metabolic fluxes during cell growth.
  
  
  CONCLUSIONS
  This work constitutes a first comprehensive systems biology study on growth-rate control in the eukaryotic cell. The results have direct implications for advanced studies on cell growth, in vivo regulation of metabolic fluxes for comprehensive metabolic engineering, and for the design of genome-scale systems biology models of the eukaryotic cell.
authors: Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors: Juan I
authors: JI
authors: Castrillo
authors: Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors: Leo A
authors: LA
authors: Zeef
authors: Northwest Institute for Bio-Health Informatics (NIBHI), School of Medicine, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors: David C
authors: DC
authors: Hoyle
authors: Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors: Nianshu
authors: N
authors: Zhang
authors: Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors: Andrew
authors: A
authors: Hayes
authors: Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors: David Cj
authors: DC
authors: Gardner
authors: Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.|School of Computer Science, Kilburn Building, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
authors: Michael J
authors: MJ
authors: Cornell
authors: Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors: June
authors: J
authors: Petty
authors: Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors: Luke
authors: L
authors: Hakes
authors: Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors: Leanne
authors: L
authors: Wardleworth
authors: Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors: Bharat
authors: B
authors: Rash
authors: School of Chemistry, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
authors: Marie
authors: M
authors: Brown
authors: Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
authors: Warwick B
authors: WB
authors: Dunn
authors: School of Chemistry, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.|Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
authors: David
authors: D
authors: Broadhurst
authors: Cambridge Centre for Proteomics, Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, UK.
authors: Kerry
authors: K
authors: O'Donoghue
authors: Cambridge Centre for Proteomics, Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, UK.
authors: Svenja S
authors: SS
authors: Hester
authors: Cambridge Centre for Proteomics, Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, UK.
authors: Tom Pj
authors: TP
authors: Dunkley
authors: School of Chemistry, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
authors: Sarah R
authors: SR
authors: Hart
authors: Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
authors: Neil
authors: N
authors: Swainston
authors: Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
authors: Peter
authors: P
authors: Li
authors: School of Chemistry, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.|Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
authors: Simon J
authors: SJ
authors: Gaskell
authors: School of Computer Science, Kilburn Building, University of Manchester, Oxford Road, Manchester M13 9PL, UK.|Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
authors: Norman W
authors: NW
authors: Paton
authors: Cambridge Centre for Proteomics, Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, UK.
authors: Kathryn S
authors: KS
authors: Lilley
authors: School of Chemistry, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.|Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
authors: Douglas B
authors: DB
authors: Kell
authors: Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.|Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess St, Manchester M1 7DN, UK.
authors: Stephen G
authors: SG
authors: Oliver
mesh_terms: D002244:Carbon / Q000378:metabolism; D018929:Cell Culture Techniques; D005057:Eukaryotic Cells / Q000502:physiology*; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000502:physiology*; D015398:Signal Transduction; D049490:Systems Biology / Q000379:methods*; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic
chemical_list: D002244:Carbon; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases