Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.771292
Title: Investigating nutrient-sensing mechanisms that control cell size at division
Author: Davie, Elizabeth
ISNI:       0000 0004 7657 3729
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2014
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Abstract:
Cell growth and cell cycle progression are tightly coordinated, allowing cells to adjust their size to the demands of proliferation in varying nutritional environments. This coordination is regulated by Target of Rapamycin (TOR) signalling. Active TOR complex 1 (TORC1) promotes cell growth to delay mitosis and increase cell size at division, whereas under limited nutrients TORC1 activity is down-regulated to advance mitosis and reduce cell size. In fission yeast Schizosaccharomyces pombe, a shift from rich to poor nitrogen environment - nitrogen stress - results in TOR inhibition, which activates MAPK signalling to promote entry into mitosis at a reduced cell size. However, it remains unclear how nitrogen stress is sensed upstream of TOR signalling to control this response. This study uses genetic and biochemical approaches to probe the mechanisms of nitrogen sensing that control cell size at division. I propose a model whereby nitrogen stress is sensed by two mechanisms that regulate the AMP-activated protein kinase (AMPK). I show that nitrogen stress reduces cellular ATP levels, suggesting that advanced mitotic entry may be promoted by detecting a reduction in cellular energy. Analysis of AMPK mutants revealed that Ssp2 (AMPKalpha) is required for cells to reduce their size in response to nitrogen stress. Moreover, activating phosphorylation of Ssp2 on Thr189 is enhanced under nitrogen-poor conditions. However, I also observe that the β-and γ-subunits of AMPK are not essential for the nitrogen-stress response, providing evidence for an additional, energy-independent mechanism of sensing changes in nitrogen quality. This work presents new evidence for the regulation of Ssp2 phosphorylation by Mph1 kinase on Thr189, and also by TORC1 on a newly characterised conserved phosphorylation site Ser367. Overall, the data suggests that activated Ssp2 can signal to modulate TORC1 activity and control cell size at division in response to nitrogen stress.
Supervisor: Woodman, Philip Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.771292  DOI: Not available
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