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Curr Biol. 2015 Feb 16;25(4):445-54. doi: 10.1016/j.cub.2014.12.034. Epub 2015 Jan 29.

Nitrogen regulates AMPK to control TORC1 signaling.

Author information

1
Faculty of Life Sciences, University of Manchester, C.4255 Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.
2
Faculty of Life Sciences, University of Manchester, C.4255 Michael Smith Building, Oxford Road, Manchester M13 9PT, UK; Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, SA 5001, Australia. Electronic address: janni.petersen@flinders.edu.au.

Abstract

BACKGROUND:

Cell growth and cell-cycle progression are tightly coordinated to enable cells to adjust their size (timing of division) to the demands of proliferation in varying nutritional environments. In fission yeast, nitrogen stress results in sustained proliferation at a reduced size.

RESULTS:

Here, we show that cells can sense nitrogen stress to reduce target of rapamycin complex-1 (TORC1) activity. Nitrogen-stress-induced TORC1 inhibition differs from amino-acid-dependent control of TORC1 and requires the Ssp2 (AMPKα) kinase, the Tsc1/2 complex, and Rhb1 GTPase. Importantly, the β and γ regulatory subunits of AMPK are not required to control cell division in response to nitrogen stress, providing evidence for a nitrogen-sensing mechanism that is independent of changes in intracellular ATP/AMP levels. The CaMKK homolog Ssp1 is constitutively required for phosphorylation of the AMPKα(Ssp2) T loop. However, we find that a second homolog CaMKK(Ppk34) is specifically required to stimulate AMPKα(Ssp2) activation in response to nitrogen stress. Finally, ammonia also controls mTORC1 activity in human cells; mTORC1 is activated upon the addition of ammonium to glutamine-starved Hep3B cancer cells.

CONCLUSIONS:

The alternative nitrogen source ammonia can simulate TORC1 activity to support growth and division under challenging nutrient settings, a situation often seen in cancer.

PMID:
25639242
PMCID:
PMC4331286
DOI:
10.1016/j.cub.2014.12.034
[Indexed for MEDLINE]
Free PMC Article

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