TRECEG · Role of NFAT5 during the transcriptional response to cellular growth
6РП — Действия „Мария Кюри“
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Накратко на български
Протеинът NFAT5 регулира начина, по който Т-лимфоцитите реагират на промени в солеността на течностите около тях. Разбирането на този механизъм помага да се разбере защо при липса на NFAT5 клетките спират да се делят и функционират неправилно.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
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.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
This proposal addresses the role of the transcription factor NFAT5 in cell growth and proliferation in normal and transformed cells. NFAT5, the latest addition to the Rel (NFATc/ NF-kB) family of transcription factors, is activated by hypertonicity, but also responds to antigen receptor stimulation in lymphocytes and integrin-induced signals in carcinoma cells, responses that involve mechanisms which at present are poorly understood. In the mouse, NFAT5 protein is expressed in most organs during embryonic development but its levels decrease dramatically in most adult tissues, except at sites with high cellular turnover, such as thymus and testis, where NFAT5 is highly expressed. In vitro, expression of NFAT5 correlates with cellular proliferation in both normal and transformed cells.NFAT5 null mice have reduced embryonic and perinatal survival, and those surviving into adulthood have a striking growth phenotype with an overall reduction of body and organ size. In addition, their life-span is severely compromised, owing in part to progressive renalatrophy as mice age, caused by defective regeneration of the kidney medulla associated to the lack of expression of NFATS-dependent osmoprotective genes. The kidney phenotype of NFAT5-null mice confirms its role in osmoprotective responses in vivo. However, it does not explain the embryonic mortality and growth defects, indicating that NFAT5 has additional, cell growth-related functions.We propose to investigate NFAT5 function by analysing cell growth-related parameters (proliferation, cell cycle, apoptosis) in normal wild type and NFAT5-null cells. Since tumor progression requires sustained proliferation, we will address whether NFAT5 might be involved in tumor formation by determining the ability of specific oncogenes to transform N FAT5 null cells, and by assessing the in vivo tumour ogenic potential of transformed wild-type and NFAT5 null cells.
Оригинален текст от CORDIS (на английски).
Участници
- FUNDACIO CENTRE DE REGULACIO GENOMICA · BARCELONAКоординаторИспания
Връзки
Данни: CORDIS, © Европейски съюз