Tonicity-independent regulation of the osmosensitive transcription factor TonEBP (NFAT5)

Abstract

Tonicity-responsive enhancer binding protein (TonEBP/nuclear factor of activated T-cells 5 [NFAT5]) is a Rel homology transcription factor classically known for its osmosensitive role in regulating cellular homeostasis during states of hypo- and hypertonic stress. A recently growing body of research indicates that TonEBP is not solely regulated by tonicity, but that it can be stimulated by various tonicity-independent mechanisms in both hypertonic and isotonic tissues. Physiological and pathophysiological stimuli such as cytokines, growth factors, receptor and integrin activation, contractile agonists, ions, and reactive oxygen species have been implicated in the positive regulation of TonEBP expression and activity in diverse cell types. These new data demonstrate that tonicity-independent stimulation of TonEBP is critical for tissue-specific functions like enhanced cell survival, migration, proliferation, vascular remodeling, carcinoma invasion, and angiogenesis. Continuing research will provide a better understanding as to how these and other alternative TonEBP stimuli regulate gene expression in both health and disease.

Two isoforms of aquaporin 2 responsive to hypertonic stress in bottlenose dolphin

“…TonEBP also participates in compatible osmolyte accumulation by upregulating relevant genes (Coleman et al, 2000;Miyakawa et al, 1998;Rim et al, 1998). The DNA sequence of the TonEBP binding site in the AQP2 promoter is GGAAA (Halterman et al, 2012); the bottlenose dolphin AQP2 proximal promoter includes this sequence at −139 and −327 bp upstream of the start codon (turTru1: GeneScaffold_1570, Ensembl Genome Blowser). The TonEBP gene is present in the bottlenose dolphin (ENSTTRG00000010017), and we confirmed that TonEBP mRNA is expressed and upregulated by addition of NaCl in dolphin renal cells.…”

NFAT5 moves to Fat City

“…Could it be that this NFAT5 regulation of CACNA1C is important throughout the life of the organism? As we found above, the signals to activate NFAT5 are many; the first found was an osmotic stimulus [2,4]. A critical question is, "what drives the mechanisms of activation here?"…”

“…Hypertonicity activates NFAT5 by increasing its nuclear localization and by transactivating its activity in the early phase and protein abundance in the late phase of activation. The inhibition of NFAT5 by hypotonicity features a decrease in nuclear NFAT5 expression.Recent evidence indicates that NFAT5 is not solely regulated by tonicity, but instead that NFAT5 can be stimulated by various tonicity-independent mechanisms in both hypertonic and isotonic tissues [4]. Cytokines, growth factors, receptor and integrin activation, contractile agonists, ions, and reactive oxygen species have all been implicated in the positive regulation of NFAT5 expression and activity in diverse cell types, notably immune cells [5].…”

Zitosoleko lipido-tanten sorrera eta erabilera

“…FSP27-k NFAT5 (nuclear factor of activated T cells 5; aktibatutako T zelulen faktore nuklearra 5) transkripzio-faktorea bahitzen du, eta nukleora sartzea oztopatuz bere jarduera murrizten du [23]. NFAT5 transkripzio-faktoreak estres hipertonikoari eta estimulu ugariri aurre egiteko erregulatzen du gene-adierazpena [24,25] eta, beraz, LTek homeostasiaren modulazioan dihardutela esan daiteke.…”