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Role of the transcription factor NFAT5 in mammalian cell cycle regulation

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dc.contributor.author Drews-Elger, Katherine, 1978-
dc.contributor.other Aramburu, José (Aramburu Beltrán)
dc.contributor.other Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut
dc.date.accessioned 2017-09-24T02:04:22Z
dc.date.available 2017-09-24T02:04:22Z
dc.date.issued 2008-11-07
dc.identifier B.14124-2009
dc.identifier 9788469274545
dc.identifier http://www.tdx.cat/TDX-1102109-130647
dc.identifier http://hdl.handle.net/10803/7177
dc.identifier.uri http://hdl.handle.net/10230/11946
dc.description.abstract The transcription factor NFAT5/TonEBP belongs to the Rel family, which also comprises NF ÛB and NFATc proteins. NFAT5 only shares structural and functional homology with other Rel family members at the level of the DNA binding domain, and differs from them considerably in other regions. NFAT5 enables mammalian cells to adapt to and withstand hypertonicity by orchestrating an osmoprotective gene expression program whose products include chaperones as well as ransporters and enzymes that increase the intracellular concentration of compatible osmolytes. NFAT5-null mice suffer severe embryonic and perinatal lethality, and surviving adults manifest growth defects, pronounced renal atrophy and lymphocyte dysfunction associated with ineffective responses to hypertonicity. To circumvent the lethality of these mice and study the function of NFAT5 in specific cell types without the possible side effects of generalized defects in the organism, we have produced conditional knockout mice that allow the deletion of NFAT5 in specific cell types. Here we have investigated the hypertonic stress response in wild-type and NFAT5-/- lymphocytes. Proliferating lymphocytes exposed to hypertonic conditions exhibited an early, NFAT5- independent, genotoxic stress-like response with induction of p53, p21 and GADD45, downregulation of cyclins E1, A2 and B1 mRNA, and arrest in S and G2/M. This was followed by an NFAT5-dependent adaptive phase in wild-type cells, which induced osmoprotective gene products, downregulated stress markers, and resumed cyclin expression and cell cycle progression. NFAT5-/- cells, however, failed to induce osmoprotective genes and though they downregulated genotoxic stress markers, they displayed defective cell cycle progression associated with reduced expression of cyclins E1, A2, B1, and aurora B kinase. Finally, T cell receptor-induced expression of cyclins, aurora B kinase, and cell cycle progression were inhibited in NFAT5-/- lymphocytes exposed to hypertonicity levels in the range reported in plasma in patients and animal models of osmoregulatory disorders. Our results support the conclusion that the activation of an osmoprotective gene expression program by NFAT5 enables cells to proliferate under hypertonic stress conditions by maintaining the expression of S and G2/M cyclins and cell cycle progression.
dc.format application/pdf
dc.language.iso eng
dc.publisher Universitat Pompeu Fabra
dc.rights ADVERTIMENT. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.
dc.rights info:eu-repo/semantics/openAccess
dc.source TDX (Tesis Doctorals en Xarxa)
dc.title Role of the transcription factor NFAT5 in mammalian cell cycle regulation
dc.type info:eu-repo/semantics/doctoralThesis
dc.type info:eu-repo/semantics/publishedVersion
dc.date.modified 2017-09-22T04:20:00Z
dc.subject.keyword DNA damage
dc.subject.keyword lymphocytes
dc.subject.keyword cyclins
dc.subject.keyword cell cycle
dc.subject.keyword hypertonicity
dc.subject.keyword osmotic stress
dc.subject.keyword NFAT5
dc.subject.keyword genotoxic stress
dc.subject.keyword T cell proliferation
dc.subject.keyword 575
dc.subject.keyword 576
dc.subject.keyword 616

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