Environmental control of cell growth and proliferation

E Davie2, G Forte2, T Wang1 and J Petersen1,2

  1. Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, SA 5001, Australia
  2. University of Manchester, C.4255 Michael Smith Building, Faculty of Life Sciences, Oxford Road, Manchester M13 9PT, UK

In order to continue to meet the demands of proliferation under environmental stress, cells have to coordinate their growth with division to match the available resources. In the presence of rich nutrients, cells maintain high levels of protein synthesis to increase biomass and promote division. The target of rapamycin (TOR) acts as a major nutrient sensor and is involved in regulating the coupling of cell growth and cell cycle progression in response to alterations in the environment. Nitrogen stress results in sustained proliferation at a reduced cell size. Fission yeast cells respond to nitrogen stress by reducing Target Of Rapamycin Complex-1 (TORC1) activity. We show that nitrogen stress-induced TORC1 inhibition differs from the well-established amino acid-dependent control of TORC1 [1]. Furthermore, it requires AMPK kinase, the Tsc1/2 complex and Rhb1 GTPase. However, the beta and gamma regulatory subunits of AMPK are not required to control cell division in response to nitrogen stress, which is indicative of a nitrogen-sensing mechanism that is independent of changes in intracellular ATP/AMP levels. Importantly nitrogen stress also differs from nitrogen starvation induced cell cycle exit, as the response to nitrogen starvation requires all three subunits of the AMPK complex. Finally we have shown that, this third, novel, amino acid independent mode of nitrogen sensing is evolutionarily conserved. We demonstrate that altered ammonia levels regulate AMPK and mTORC1 activity in mammalian cells and that ammonia can be used as an alternative nitrogen source to support the proliferation of transformed cells. Thus, the availability of ammonia as a nitrogen source is likely to expand the survival mechanisms available to cells under nutrient stress.
References: [1] Davie E, Forte GM, Petersen J. Nitrogen regulates AMPK to control TORC1 signalling. Current Biology. 2015; 25:445-454.