Visit our Expo - Redox and Inflammation signaling 2012

Regulation of the cell cycle by the transcription factor NFAT5 in response to osmotic
and genotoxic stress.
Jose Aramburu, Katherine Drews, Beatriz Morancho and Cristina López-Rodriguez.
Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003
Barcelona, Spain. E-mail: jaramburu@imim.es; katherine.drews@upf.edu;
beatriz.morancho@upf.edu; cristina.lopez-rodriguez@upf.edu.
The transcription factor NFAT5 belongs to the Rel family, that comprises NF-kappaB and the
calcineurin-activated NFATc proteins (1). NFAT5 is activated by hypertonicity and regulates
the expression of osmoprotective genes, but also responds to mitogenic signals and is
expressed in proliferating cells (2, 3). As osmotic stress can cause DNA breaks, and activation
of NFAT5 by hypertonicity is regulated by PI3-kinase related kinases (PIKK) (4), which
control cellular responses to DNA damage, we hypothesized that NFAT5 might play a role in
the cellular response to genotoxic stress. Cell cycle arrest is a hallmark of genotoxic stress and
is often exacerbated by the disruption of proteins involved in DNA damage sensing and
repair. We have studied whether the inhibition of NFAT5 had an effect in the cell cycle of
cells exposed to osmotic and genotoxic stress. Our results showed that proliferating NFAT5-/-
T cells did not display substantial cell cycle defects under non-stress conditions, but arrested
at G1 and G2/M when subjected to hypertonicity and ionizing radiation doses that did not
arrest wild-type T lymphocytes. Likewise, suppression of NFAT5 with shRNA in HEK293
cells caused them to accumulate in G2/M when exposed to hypertonic stress or ionizing
radiation. We found that ionizing radiation and the genotoxic drugs etoposide and
hidroxyurea caused NFAT5 to accumulate in the nucleus in HEK293 cells and that its
overexpression rendered cells more resistant to cell cycle arrest when exposed to
hypertonicity or ionizing radiation. Our results indicate that NFAT5 can regulate the cell
cycle in response to genotoxic stress, and we are currently exploring the mechanisms
underlying this function.
References.
1) López-Rodríguez C, Aramburu J, Rakeman AS, Copeland NG, Gilbert DJ, Thomas S,
Disteche C, Jenkins NA, and Rao A. 1999. NF-AT5: the NF-AT family of transcription
factors expands in a new direction. Cold Spring Harb Symp Quant Biol. 1999; 64:517-526.
2) López-Rodríguez C, Aramburu J, Jin L, Rakeman AS, Michino M, Rao A. 2001. Bridging
the NFAT and NF-kappaB families: NFAT5 dimerization regulates cytokine gene
transcription in response to osmotic stress. Immunity. 15:47-58.
3) López-Rodríguez C, Antos C. L, Shelton J, Richardson J. A, Fangming L, Novobrantseva
T. I, Bronson R.T, Igarashi P, Rao A, and Olson E. N. 2004. Loss of NFAT5 results in renal
atrophy and lack of tonicity-responsive gene expression. Proc. Natl Acad of Sci USA. 101;
2392-2397.
4) Irarrazabal C.E, Liu J.C, Burg M.B, and Ferraris J.D. 2004. ATM, a DNA damageinducible
kinase, contributes to activation by high NaCl of the transcription factor
TonEBP/OREBP. Proc. Natl. Acad. Sci. U. S. A 101, 8809-8814.
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