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Content archived on 2024-05-29

Role of NFAT5 during the transcriptional response to cellular growth

Objective

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.

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Call for proposal

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FP6-2002-MOBILITY-12
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Funding Scheme

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IRG - Marie Curie actions-International re-integration grants

Coordinator

FUNDACIO CENTRE DE REGULACIO GENOMICA
EU contribution
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Total cost

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