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Nutrient signal transduction and control of quisecence in yeast

English title Nutrient signal transduction and control of quisecence in yeast
Applicant De Virgilio Claudio
Number 115991
Funding scheme Project funding (Div. I-III)
Research institution Dépt Microbiologie et Médecine Moléculaire Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Molecular Biology
Start/End 01.08.2007 - 31.07.2010
Approved amount 604'369.00
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All Disciplines (3)

Discipline
Molecular Biology
Cellular Biology, Cytology
Experimental Microbiology

Keywords (6)

growth control; cell proliferation; nutrient signal transduction; PKA; TOR; Sch9

Lay Summary (English)

Lead
Lay summary
AimsAll living cells are capable of exiting the normal cell cycle (proliferating state) and entering an alternative (resting) state termed quiescence or G0. Despite the fact that most eukaryotic cells - whether they exist as single cells or as part of a multicellular organism - spend most of their life in a quiescent state, relatively little is known about the regulatory mechanisms that control entry into or exit from such a state. The available body of data, nevertheless, indicates that disruption of G0-entry/exit control mechanisms is often associated with either cellular transformation (particularly in multicellular organisms), or dramatically reduced life span (of unicellular organisms). In this context, we propose to continue our studies of the mechanisms controlling entry into, survival in, and exit from quiescence in the unicellular, eukaryotic model organism S. cerevisiae. So far, several studies (including ours) have uncovered that the nutrient-regulated hub TORC1 orchestrates both entry into and exit from G0. Our research is therefore specifically focused on the elucidation of both the mechanisms that regulate TORC1 activity and the nature of the effectors that are regulated by TORC1.Context and significanceHyperactivation of mammalian TORC1 (mTORC1) has been implicated in a number of cancers and cancer predisposition hypertrophic syndromes. Identification of the conserved pathways that impinge on, or that are regulated by TORC1, are therefore likely to significantly contribute not only to our basic understanding of these fundamental processes, but also to the development of both diagnostic and therapeutic tools for the treatment of diseases associated with hyperactivated mTORC1.Methodological approachesWe have previously demonstrated that TORC1 indirectly regulates Rim15, a distinct member of the large tumor suppressor (LATS) serine/threonine kinase subclass of AGC protein kinases, which functions as a key modulator of many aspects of the G0 program. In a first set of experimental approaches, we will carry our detailed structural and functional analyses of Rim15. In complementary and parallel efforts, we will then investigate the downstream mechanisms controlled by Rim15 by pursuing detailed biochemical, genetic and physiological studies of the human endosulfine homologs Igo1 and Igo2 (for initiation of G0), which we recently identified as bona fide key targets of Rim15.In a search for mutants that exhibit a specific defect in exit from quiescence, we recently discovered the vacuolar membrane-associated EGO protein complex, which likely relays critical nutrient signals from the vacuolar compartment to TORC1. In a second set of experimental approaches, we propose an array of biochemical, genetic and systems-driven experiments that will address the functional relationship between the EGO complex and TORC1, the nature of the nutrient signal(s) and the corresponding regulatory mechanism(s) that control EGO complex function.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
106754 Nutrient-regulated protein kineases and cell proliferation control in yeast 01.08.2005 SNSF Professorships
131085 Nutrient signal transduction and control of quiescence in yeast 01.08.2010 Project funding (Div. I-III)
121308 High resolution mass spectrometry for in vivo characterization of bioactive compounds for brain and tumor research 01.10.2008 R'EQUIP

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