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Final Activity Report Summary - TRECEG (Role of NFAT5 during the transcriptional response to cellular growth)

Diverse forms of stress, either environmental or intrinsic to the cell, can disrupt cellular functions, impairing cell growth, viability and proliferative capacity. Defects in the cellular responses to stress can lead to exacerbated sensitivity to stressors and accelerated cell degeneration and death, or inappropriate survival of cells with damaged genetic material, at increased risk of transformation. The transcription factor NFAT5 belongs to the Rel protein family, which comprises NF-kB and NFATc proteins. NFAT5 plays a fundamental role in the response of mammalian cells to hypertonic stress by inducing the expression of enzymes and solute carriers that allow cells to maintain an appropriate intracellular osmolality when exposed to extracellular hypertonic conditions. In this regard, NFAT5-deficient mice suffer severe renal defects and impaired lymphocyte function associated to ineffective responses to hypertonicity.

Despite of this, little is known about processes controlled by NFAT5 that allow primary cells to maintain their function under physiologic or pathologic alterations of extracellular tonicity in mammalian organisms. Our current work shows that hypertonicity levels in the range measured in the plasma of patients with hypernatremia and osmoregulatry disorders induce a robust activation of NFAT5 transcriptional activity in normal T lymphocytes, but cause cell cycle arrest and defects in the function of cell cycle regulators in NFAT5-deficient T cells. Since lymphocytes must grow and proliferate as part of their natural response to antigenic stimulation, they provide a relevant cell model to study the effect of physiopathologic conditions of osmotic stress not only during the immune response, but also in basic aspects of cellular metabolism and cell cycle progression. In this project we have characterised the role of NFAT5 in the expression of cell cycle regulators and signalling pathways involved in cell growth in response to pathologic alterations of the osmotic balance.

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