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Role of Gcn4p in Nutrient-Controlled Gene Expression in Saccharomyces Cerevisiae

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Role of Gcn4p in Nutrient-Controlled Gene Expression in Saccharomyces Cerevisiae Role of Gcn4p in nutrient-controlled gene expression in Saccharomyces cerevisiae Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultäten der Georg-August-Universität vorgelegt von Olav Grundmann aus Göttingen Göttingen 2001 D7 Referent: Prof. Dr. G. H. Braus Korreferent: Prof. Dr. F. Mayer Tag der mündlichen Prüfung: 27.Juni.2001 Table of Contents I Table of Contents Summary................................................................................................................ 1 Zusammenfassung.............................................................................................. 3 Chapter I: Introduction.......................................................................................................... 5 Regulation of morphology of the bakers’ yeast Saccharomyces cerevisiae in dependence on the nutritional conditions.............................................................. 5 Life cycle of Saccharomyces cerevisiae.............................................................. 5 Pseudohyphal growth of Saccharomyces cerevisiae......................................... 6 Environmental stimuli and sensing systems..................................................... 7 Signaling pathways............................................................................................. 8 FLO11 is indispensable for filamentous growth.............................................. 11 Why studying pseudohyphal development in Saccharomyces cerevisiae?.... 12 Regulation of amino acid biosynthesis in the yeast Saccharomyces cerevisiae........................................................................................ 13 General control of amino acid biosynthesis..................................................... 13 General structure of DNA binding transcription factors............................... 14 Gcn4p is the final effector of the general control in Saccharomyces cerevisiae................................................................................... 15 Initiation of translation and its regulation in eukaryotes............................... 16 Translational control of GCN4 expression....................................................... 19 Aim of this work...................................................................................................... 23 References................................................................................................................ 24 Table of Contents II Chapter II: Repression of GCN4 mRNA translation by nitrogen starvation in S. cerevisiae............................................................................................................ 31 Summary................................................................................................................... 31 Introduction.............................................................................................................. 32 Materials & Methods............................................................................................... 34 Results....................................................................................................................... 40 Discussion.................................................................................................................. 58 References................................................................................................................. 61 Chapter III: Amino acid starvation and Gcn4p activate adhesion and FLO11 gene expression in yeast.................................................................................... 65 Summary................................................................................................................... 65 Introduction.............................................................................................................. 66 Materials & Methods............................................................................................... 68 Results....................................................................................................................... 72 Discussion.................................................................................................................. 88 References................................................................................................................. 92 Table of Contents III Chapter IV: Genome-wide transcription profile analysis of Gcn4p-dependent gene transcription under amino acid starvation conditions in Saccharomyces cerevisiae.................................................................................. 96 Summary................................................................................................................... 96 Introduction.............................................................................................................. 97 Materials & Methods............................................................................................... 99 Results....................................................................................................................... 101 Discussion.................................................................................................................. 106 References................................................................................................................. 141 Lebenslauf.............................................................................................................. 145 Summary 1 Summary Under amino acid starvation conditions, the bakers’ yeast Saccharomyces cerevisiae activates a system called “General control of amino acid biosynthesis”. Gcn4p, the transcription factor of this system induces the expression of more than 50 genes involved in the different amino acid biosynthetic pathways. In this thesis it could be shown that during simultaneous limitation of amino acids and nitrogen the general control is not activated. More exactly, even a decrease of the Gcn4p activity was detected, which was traced back onto a reduction of the Gcn4 protein amount in the cell. This decrease of the intracellular concentration was caused by translational control of the GCN4 mRNA, which was able to repress even a 2-fold increase of the GCN4 transcription rate. Furthermore during nitrogen starvation conditions no correlation between the stature of eIF-2 phosphorylation and GCN4 expression was observed. For this reason an involvement of the already known mechanism of translational regulation of GCN4 mRNA could be excluded. Rather a factor is postulated, which is situated downstream of eIF-2 and has a regulatory effect on initiation of translation. Although it could be proven that the Gcn4p activity is repressed during amino acid starvation, a gcn4 mutant strain was not able to form pseudohyphae any more. This indicated to a dependence of pseudohyphal growth on the presence of Gcn4p. Furthermore it was detected that the transcription of FLO11, which is a flocculin gene necessary for pseudohyphal growth, was activated by amino acid limitation under normal nitrogen concentrations as well. This activation is Gcn4p-dependent and leads to an improved cell-cell adhesion. Gcn4p as well as the transcription factor of the cAMP pathway, Flo8p are necessary for FLO11 expression during amino acid limitation. On the other hand the transcription factors of the MAPK pathway, Ste12p and Tec1p, which are important under nitrogen starvation conditions as well have only a minor importance. By comparative transcriptome analysis of a yeast wild type and a gcn4 mutant strain, which were grown under amino acid limitation conditions, 225 genes were identified, which were Gcn4p-dependent activated during amino acid starvation conditions. Not only genes of amino acid or nucleotide metabolism, for which a Gcn4p- dependent transcription was already known, but also several other genes were identified, which are involved in completely different cellular processes. A Gcn4p- Summary 2 dependent activation of transcription could be detected for genes of carbon, fatty acid and phosphorus metabolism, as well as for genes coding for chromatin structure determining proteins (e.g. histones). Zusammenfassung 3 Zusammenfassung Unter Aminosäure-Mangelbedingungen schaltet die Bäckerhefe Saccharomyces cerevisiae die sogenannte „Allgemeine Kontrolle der Aminosäure- Biosynthese“ ein. Gcn4p, der Transkriptionsfaktor dieses Systems, aktiviert die Expression von über 50 Genen, die in die verschiedenen Aminosäure-Biosynthesewege involviert sind. Im Rahmen dieser Arbeit konnte gezeigt werden, daß bei gleichzeitiger Limitierung von Aminosäuren und Stickstoff, die Allgemeine Kontrolle der Aminosäure-Biosynthese nicht aktiviert wird. Vielmehr konnte eine Abnahme der Gcn4p-Aktivität beobachtet werden, die auf eine Verminderung der Gcn4-Proteinmenge zurückzuführen war. Ursache für diese Abnahme der intrazellulären Proteinkonzentration war die translationelle Kontrolle der GCN4-mRNA, die selbst eine unter diesen Bedingungen auftretende zweifache Erhöhung der GCN4- Transkriptionsrate repremieren konnte. Außerdem wurde gezeigt, daß unter Stickstoff- Mangelbedingungen keine Korrelation zwischen dem Phosphorylierungsstatus von eIF- 2 und der GCN4-Expression mehr gegeben war. Dadurch konnte ausgeschlossen werden, daß der bereits bekannte Mechanismus der translationellen Kontrolle der GCN4-mRNA unter diesen Bedingungen eine Rolle spielt. Vielmehr wird ein zusätzlicher Faktor postuliert, der unterhalb von eIF-2 direkt auf
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