Regulation of Gene Expression by Hypertonicity

Burg, Maurice B.; Kwon, Eugene D.; Kültz, Dietmar

doi:10.1146/annurev.physiol.59.1.437

Cited by 352 publications

(303 citation statements)

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“…1F). Mitogen-activated protein kinases signal organic osmolyte accumulation in yeast and mammals (12,39). Genetic epistasis analysis suggests that calmodulin-dependent and p38 MAPK cascades may function downstream from osr-1 to mediate osmotic stress resistance (Fig.…”

Section: R180 Salt and Water Homeostasis In C Elegansmentioning

confidence: 99%

Physiological and molecular mechanisms of salt and water homeostasis in the nematodeCaenorhabditis elegans

Choe

2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Choe KP. Physiological and molecular mechanisms of salt and water homeostasis in the nematode Caenorhabditis elegans. Am J Physiol Regul Integr Comp Physiol 305: R175-R186, 2013. First published June 5, 2013 doi:10.1152/ajpregu.00109.2013.-Intracellular salt and water homeostasis is essential for all cellular life. Extracellular salt and water homeostasis is also important for multicellular organisms. Many fundamental mechanisms of compensation for osmotic perturbations are well defined and conserved. Alternatively, molecular mechanisms of detecting salt and water imbalances and regulating compensatory responses are generally poorly defined for animals. Throughout the last century, researchers studying vertebrates and vertebrate cells made critical contributions to our understanding of osmoregulation, especially mechanisms of salt and water transport and organic osmolyte accumulation. Researchers have more recently started using invertebrate model organisms with defined genomes and well-established methods of genetic manipulation to begin defining the genes and integrated regulatory networks that respond to osmotic stress. The nematode Caenorhabditis elegans is well suited to these studies. Here, I introduce osmoregulatory mechanisms in this model, discuss experimental advantages and limitations, and review important findings. Key discoveries include defining genetic mechanisms of osmolarity sensing in neurons, identifying protein damage as a sensor and principle determinant of hypertonic stress resistance, and identification of a putative sensor for hypertonic stress associated with the extracellular matrix. Many of these processes and pathways are conserved and, therefore, provide new insights into salt and water homeostasis in other animals, including mammals. osmoregulation; cell volume; ion; organic osmolyte; protein homeostasis; model organism SALT AND WATER HOMEOSTASIS is a fundamental requirement for metazoan life. Ion and water transport mechanisms that compensate for changes in composition and volume of intracellular and extracellular compartments have been generally well defined using vertebrate cell and in vivo models (38). Alternatively, the upstream molecular mechanisms that animal cells use to sense deviations in salt and water balance and regulate compensatory responses are still poorly characterized (20). Studies in brewer's yeast demonstrate that osmotic signal detection and transduction within a single eukaryotic cell can be highly complex with numerous components, acting in parallel pathways, that often cross-talk with other processes (40,55). Osmotic signal detection and transduction are likely to be even more complex in metazoans, which require homeostasis of both the extracellular and intracellular compartments and integration of responses between cells. Genetics is an extremely powerful approach for identifying and characterizing genes and proteins that function in complex biological processes but has been underutilized in the field of osmosensing and signal transduction in metazoans. In...

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Section: R180 Salt and Water Homeostasis In C Elegansmentioning

confidence: 99%

Physiological and molecular mechanisms of salt and water homeostasis in the nematodeCaenorhabditis elegans

Choe

2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The data shown are representative of at least three independent experiments. which maintain intracellular isotonicity within a hyperosmotic environment (41). Cell lines (e.g., MDCK and HeLa) subject to hyperosmotic conditions induce NFATL1 protein expression, DNA binding activity, and NFATL1-dependent transcription (25,27).…”

Section: Receptor-dependent Induction Of Nfatl1mentioning

confidence: 99%

“…Mammalian cells respond to hyperosmotic conditions in culture by initiating a pleiotropic response that includes induction of heat shock proteins, activation of the p38, stress-activated protein kinase/c-Jun N-terminal kinase (JNK), and extracellular signal-related kinase mitogen-activated protein kinase (MAPK) pathways, and transcription of tonicity-responsive osmoregulatory genes (41). Although the initial identification of NFATL1 as a TonEBP that is induced in response to hyperosmolar conditions provides an additional signaling intermediate potentially linking upstream events with defined transcriptional responses, the mechanisms resulting in the induction of NFATL1 by hyperosmotic stimuli remain unclear.…”

Section: Signaling Mechanisms Regulating Nfatl1 Expressionmentioning

confidence: 99%

“…Thus, one possible role of NFATL1 induced upon receptor-dependent cellular activation that is suggested by its role in regulating transcriptional responses to hyperosmotic conditions would be to regulate the transcription of genes involved in maintaining osmotic homeostasis in response to the increase in cell volume that occurs during lymphocyte activation. A hyperosmotic stimulus, particularly that used experimentally in cell culture, induces a rapid reduction of cell volume, which results in the concentration of intracellular macromolecules and rapid uptake of inorganic salts (41). Activation of signaling mechanisms in this context likely results from the nonspecific, ligand-independent receptor clustering that has been observed to occur upon hyperosmotic stimulation (52).…”

Section: What Is the Function Of Nfatl1 In Receptor-dependent Cell Acmentioning

confidence: 99%

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The NFAT-Related Protein NFATL1 (TonEBP/NFAT5) Is Induced Upon T Cell Activation in a Calcineurin-Dependent Manner

Trama

Hawley

et al. 2000

The Journal of Immunology

147

168

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NFAT DNA binding complexes regulate programs of cellular activation and differentiation by translating receptor-dependent signaling events into specific transcriptional responses. NFAT proteins, originally defined as calcium/calcineurin-dependent regulators of cytokine gene transcription in T lymphocytes, are expressed in many different cell types and represent critical signaling intermediates that mediate an increasingly wide spectrum of biologic responses. Recent studies have identified a novel protein containing a region of similarity to the NFAT DNA binding domain. Here we demonstrate that this protein, designated NFATL1 (also known as tonicity enhancer binding protein and NFAT5) is expressed at high levels in the thymus but is undetectable in mature lymphocytes. However, NFATL1 can be induced in both primary quiescent T lymphocytes and differentiated Th1 and Th2 cell populations upon mitogen- or Ag receptor-dependent activation. The induction of NFATL1 protein, as well as NFATL1-dependent transcription, is inhibited by cyclosporin A and FK506, and expression of constitutively active calcineurin induces NFATL1-dependent transcription. Overexpression of NFATc1 and inhibition of NFATc activity through the use of a dominant negative NFATc1 protein have no affect on NFATL1-dependent transcription, indicating that NFATc proteins do not play a role in the calcineurin-dependent induction of NFATL1. Interestingly, induction of NFATL1 by a hyperosmotic stimulus is not blocked by the inhibition of calcineurin. Moreover, osmotic stress response genes such as aldose reductase are not induced upon T cell activation. Thus inducible expression of NFATL1 represents a mechanism by which receptor-dependent signals as well as osmotic stress signals are translated into transcriptional responses that regulate cell function.

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“…The accumulation of these compatible organic osmolytes compensates for the cell volume reduction induced by hypertonic stress by allowing the osmotic influx of water into the cell. It is speculated to be an important component of the osmotic-stress response pathway, as it was discovered in renal medulla [10,11]. However, the expression of NFAT5 is not limited to the kidney, but in fact is ubiquitous.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of NFAT5 by RNA interference reduces monoclonal antibody productivity of hybridoma cells

Zou

Xie

2007

Cell Res

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Hybridoma cells display an increase in antibody productivity following exposure to hypertonic conditions. However, the underlying mechanism is not well understood. In the present study, we hypothesize that the nuclear factor of activated T cells 5 (NFAT5)/tonicity enhancer binding protein (TonEBP) functions to increase the antibody productivity of hybridoma cells. NFAT5 is an osmosensitive mammalian transcription factor. However, its ubiquitous expression in various organs that are not bathed in hypertonic milieu suggests that NFAT5 may also regulate cell growth and function under isotonic conditions. In this study, we examined the expression of NFAT5 in hybridoma cells by Western blot analysis, and found that it increased significantly in hypertonic medium. To further define the function of NFAT5 in hybridoma cells, RNA interference technique was used to downregulate the expression of NFAT5 in SGB-8 cells (a hybridoma cell line). In isotonic medium, antibody productivity of hybridoma cells was reduced by downregulation of NFAT5 while cell proliferation was not influenced. The results presented here demonstrate that NFAT5 not only plays an important role in osmotic stress response pathway in hybridoma cells but also is essential for optimal antibody productivity.

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Regulation of Gene Expression by Hypertonicity

Cited by 352 publications

References 57 publications

Physiological and molecular mechanisms of salt and water homeostasis in the nematodeCaenorhabditis elegans

Physiological and molecular mechanisms of salt and water homeostasis in the nematodeCaenorhabditis elegans

The NFAT-Related Protein NFATL1 (TonEBP/NFAT5) Is Induced Upon T Cell Activation in a Calcineurin-Dependent Manner

Downregulation of NFAT5 by RNA interference reduces monoclonal antibody productivity of hybridoma cells

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