Although stress can suppress growth and proliferation, cells can induce adaptive responses that allow them to maintain these functions under stress. While numerous studies have focused on the inhibitory effects of stress on cell growth, less is known on how growth-promoting pathways influence stress responses. We have approached this question by analyzing the effect of mammalian target of rapamycin (mTOR), a central growth controller, on the osmotic stress response. Our results showed that mammalian cells exposed to moderate hypertonicity maintained active mTOR, which was required to sustain their cell size and proliferative capacity. Moreover, mTOR regulated the induction of diverse osmostress response genes, including targets of the tonicity-responsive transcription factor NFAT5 as well as NFAT5-independent genes. Genes sensitive to mTOR-included regulators of stress responses, growth and proliferation. Among them, we identified REDD1 and REDD2, which had been previously characterized as mTOR inhibitors in other stress contexts. We observed that mTOR facilitated transcription-permissive conditions for several osmoresponsive genes by enhancing histone H4 acetylation and the recruitment of RNA polymerase II. Altogether, these results reveal a previously unappreciated role of mTOR in regulating transcriptional mechanisms that control gene expression during cellular stress responses.

Ministry of Science and Innovation of Spain (Grant numbers BFU2008-01070, SAF2011-24268) and Distinció de la Generalitat de Catalunya per a la Promoció de la Recerca Universitària (to J.A.); the Ramón y Cajal and I3 Researcher Programmes and Ministry of Science and Innovation of Spain (Grant numbers SAF2006-04913, SAF2009-08066) and Marie Curie International Reintegration Programme (Grant number MCIRG 516308 to C.L-R.); Fundació la Marató TV3 (Grant numbers 030230/31, 080730), Spanish Ministry of Health (Fondo de Investigación Sanitaria, Red HERACLES) (Grant number RD06/ 0009/1005. FEDER) and Generalitat de Catalunya (Grant numbers SGR-00478, 2009 SGR 601) for research in the laboratories of C. L-R. and J.A.; FPI predoctoral fellowship of the Ministry of Science and Innovation of Spain (to M.C.O.); FI predoctoral fellowship from the Generalitat de Catalunya (to B.M.); FI-IQUC predoctoral fellowship from the Generalitat de Catalunya (to K.D.-E.). Funding for open access charge: Ministry of Science and Innovation of Spain (Grant numbers BFU2008-01070, SAF2011-24268 to J.A.).