Cellular osmoregulation: beyond ion transport and cell volume.

All cells are characterized by the expression of osmoregulatory mechanisms, although the degree of this expression is highly variable in different cell types even within a single organism. Cellular osmoregulatory mechanisms constitute a conserved set of adaptations that offset antagonistic effects of altered extracellular osmolality/environmental salinity on cell integrity and function. Cellular osmoregulation includes the regulation of cell volume and ion transport but it does not stop there. We know that organic osmolyte concentration, protein structure, cell turnover, and other cellular parameters are osmoregulated as well. In this brief review two important aspects of cellular osmoregulation are emphasized: 1) maintenance of genomic integrity, and 2) the central role of protein phosphorylation. Novel insight into these two aspects of cellular osmoregulation is illustrated based on two cell models, mammalian kidney inner medullary cells and teleost gill epithelial cells. Both cell types are highly hypertonicity stress-resistant and, therefore, well suited for the investigation of osmoregulatory mechanisms. Damage to the genome is discussed as a newly discovered aspect of hypertonic threat to cells and recent insights on how mammalian kidney cells deal with such threat are presented. Furthermore, the importance of protein phosphorylation as a core mechanism of osmosensory signal transduction is emphasized. In this regard, the potential roles of the 14-3-3 family of phospho-protein adaptor molecules for cellular osmoregulation are highlighted primarily based on work with fish gill epithelial cells. These examples were chosen for the reader to appreciate the numerous and highly specific interactions between stressor-specific and non-specific pathways that form an extensive cellular signaling network giving rise to adaptive compensation of hypertonicity. Furthermore, the example of 14-3-3 proteins illustrates that a single protein may participate in several pathways that are non-specific with regard to the type of stress and, at the same time, in stress-specific pathways to promote cell integrity and function during hypertonicity.

[1]  T. Adilakshmi,et al.  A novel 14-3-3 gene is osmoregulated in gill epithelium of the euryhaline teleost Fundulus heteroclitus. , 2001, The Journal of experimental biology.

[2]  D. Kültz,et al.  Mitogen-activated protein kinases are in vivo transducers of osmosensory signals in fish gill cells. , 2001, Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology.

[3]  D. Chakravarty,et al.  Hyperosmolality in the form of elevated NaCl but not urea causes DNA damage in murine kidney cells. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[4]  M. S. Trofimova,et al.  Involvement of 14-3-3 proteins in the osmotic regulation of H+-ATPase in plant plasma membranes , 2000, Planta.

[5]  Mong-Hong Lee,et al.  Association of the Cyclin-dependent Kinases and 14-3-3 Sigma Negatively Regulates Cell Cycle Progression* , 2000, The Journal of Biological Chemistry.

[6]  C. Mitchell,et al.  Phosphoinositide 3-kinase forms a complex with platelet membrane glycoprotein Ib-IX-V complex and 14-3-3ζ , 2000 .

[7]  S R Datta,et al.  14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation. , 2000, Molecular cell.

[8]  D. Kültz,et al.  Protection of Renal Inner Medullary Epithelial Cells from Apoptosis by Hypertonic Stress-induced p53 Activation* , 2000, The Journal of Biological Chemistry.

[9]  S. K. Woo,et al.  Bidirectional regulation of tonicity-responsive enhancer binding protein in response to changes in tonicity. , 2000, American journal of physiology. Renal physiology.

[10]  P. Hanawalt,et al.  p53-Mediated DNA Repair Responses to UV Radiation: Studies of Mouse Cells Lacking p53, p21, and/orgadd45 Genes , 2000, Molecular and Cellular Biology.

[11]  M. Waye,et al.  Modulation of the Ca2+-Activated Cl− Channel by 14-3-3ε , 2000 .

[12]  Y Taya,et al.  A DNA damage signal is required for p53 to activate gadd45. , 2000, Cancer research.

[13]  C. Chow,et al.  Integration of Calcium and Cyclic AMP Signaling Pathways by 14-3-3 , 2000, Molecular and Cellular Biology.

[14]  A. Stensballe,et al.  Binding of 14-3-3 Protein to the Plasma Membrane H+-ATPase AHA2 Involves the Three C-terminal Residues Tyr946-Thr-Val and Requires Phosphorylation of Thr947 * , 1999, The Journal of Biological Chemistry.

[15]  Booij,et al.  14-3-3 proteins double the number of outward-rectifying K+ channels available for activation in tomato cells , 1999, The Plant journal : for cell and molecular biology.

[16]  H. Betz,et al.  Dominant‐negative alleles of 14‐3‐3 proteins cause defects in actin organization and vesicle targeting in the yeast Saccharomyces cerevisiae , 1999, FEBS letters.

[17]  C. Brugnara,et al.  Serine/threonine protein phosphatases and regulation of K-Cl cotransport in human erythrocytes. , 1999, American journal of physiology. Cell physiology.

[18]  K. Kinzler,et al.  14-3-3σ is required to prevent mitotic catastrophe after DNA damage , 1999, Nature.

[19]  William F. Morgan,et al.  Genomic instability in Gadd45a-deficient mice , 1999, Nature Genetics.

[20]  Wei Zhang,et al.  CR6: A third member in the MyD118 and Gadd45 gene family which functions in negative growth control , 1999, Oncogene.

[21]  T. Hirano,et al.  A Novel Oncostatin M-inducible Gene OIG37 Forms a Gene Family with MyD118 and GADD45 and Negatively Regulates Cell Growth* , 1999, The Journal of Biological Chemistry.

[22]  A. Tanigami,et al.  Molecular cloning, expression, and mapping of a novel human cDNA, GRP17, highly homologous to human gadd45 and murine MyD118 , 1999, Journal of Human Genetics.

[23]  H. Fu,et al.  Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14-3-3 proteins. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[24]  S. Masters,et al.  Interaction of 14-3-3 with a nonphosphorylated protein ligand, exoenzyme S of Pseudomonas aeruginosa. , 1999, Biochemistry.

[25]  I. Levitan,et al.  A Dynamically Regulated 14–3–3, Slob, and Slowpoke Potassium Channel Complex in Drosophila Presynaptic Nerve Terminals , 1999, Neuron.

[26]  N. Walworth,et al.  Association of Chk1 with 14-3-3 proteins is stimulated by DNA damage. , 1999, Genes & development.

[27]  Harukazu Suzuki,et al.  Molecular cloning of rat GADD45γ, gene induction and its role during neuronal cell death , 1999 .

[28]  S. K. Woo,et al.  Tonicity-responsive enhancer binding protein, a rel-like protein that stimulates transcription in response to hypertonicity. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[29]  T. Myers,et al.  Gadd45, a p53-Responsive Stress Protein, Modifies DNA Accessibility on Damaged Chromatin , 1999, Molecular and Cellular Biology.

[30]  D. Cohen.  SIGNALLING AND GENE REGULATION BY UREA AND NaCl IN THE RENAL MEDULLA , 1999, Clinical and experimental pharmacology & physiology.

[31]  T. Berl,et al.  In vivo regulation of MAP kinases in Ratus norvegicus renal papilla by water loading and restriction. , 1998, The Journal of clinical investigation.

[32]  H. Saito,et al.  A Family of Stress-Inducible GADD45-like Proteins Mediate Activation of the Stress-Responsive MTK1/MEKK4 MAPKKK , 1998, Cell.

[33]  Knauth Lp.  Salinity history of the Earth's early ocean , 1998 .

[34]  Francesc Posas,et al.  Requirement of STE50 for Osmostress-Induced Activation of the STE11 Mitogen-Activated Protein Kinase Kinase Kinase in the High-Osmolarity Glycerol Response Pathway , 1998, Molecular and Cellular Biology.

[35]  Jonathan Cooper,et al.  A Novel Sphingosine-dependent Protein Kinase (SDK1) Specifically Phosphorylates Certain Isoforms of 14-3-3 Protein* , 1998, The Journal of Biological Chemistry.

[36]  S. Grinstein,et al.  Activation of protein kinases upon volume changes: role in cellular homeostasis. , 1998, Contributions to nephrology.

[37]  E. Stavridi,et al.  ATM-dependent activation of p53 involves dephosphorylation and association with 14-3-3 proteins , 1998, Nature Genetics.

[38]  D. Kültz,et al.  Hyperosmolality Causes Growth Arrest of Murine Kidney Cells , 1998, The Journal of Biological Chemistry.

[39]  R. Quatrano,et al.  14-3-3 Proteins Are Part of an Abscisic Acid–VIVIPAROUS1 (VP1) Response Complex in the Em Promoter and Interact with VP1 and EmBP1 , 1998, Plant Cell.

[40]  E. Rogakou,et al.  DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139* , 1998, The Journal of Biological Chemistry.

[41]  F. Schliess,et al.  Hyperosmotic induction of the mitogen-activated protein kinase phosphatase MKP-1 in H4IIE rat hepatoma cells. , 1998, Archives of biochemistry and biophysics.

[42]  L. Baunsgaard,et al.  The 14-3-3 proteins associate with the plant plasma membrane H(+)-ATPase to generate a fusicoccin binding complex and a fusicoccin responsive system. , 1998, The Plant journal : for cell and molecular biology.

[43]  P. Yakowec,et al.  14-3-3 proteins act as negative regulators of the mitotic inducer Cdc25 in Xenopus egg extracts. , 1998, Molecular biology of the cell.

[44]  C. Mitchell,et al.  Activation of the 43 kDa inositol polyphosphate 5-phosphatase by 14-3-3zeta. , 1997, Biochemistry.

[45]  K. Kinzler,et al.  14-3-3σ Is a p53-Regulated Inhibitor of G2/M Progression , 1997 .

[46]  B. R. Dey,et al.  14-3-3 proteins interact with the insulin-like growth factor receptor but not the insulin receptor. , 1997, The Biochemical journal.

[47]  M. Palmgren,et al.  The 14-3-3 protein interacts directly with the C-terminal region of the plant plasma membrane H(+)-ATPase. , 1997, The Plant cell.

[48]  I. Dahse,et al.  Over‐expression of plant 14‐3‐3 proteins in tobacco: enhancement of the plasmalemma K+ conductance of mesophyll cells 1 2 , 1997, FEBS letters.

[49]  J. Handler,et al.  Kidney cell survival in high tonicity. , 1997, Comparative biochemistry and physiology. Part A, Physiology.

[50]  S. E. Bonga.  The stress response in fish , 1997 .

[51]  D. Kültz,et al.  Distinct Regulation of Osmoprotective Genes in Yeast and Mammals , 1997, The Journal of Biological Chemistry.

[52]  P. O'Connor,et al.  Antisense GADD45 expression results in decreased DNA repair and sensitizes cells to u.v.-irradiation or cisplatin. , 1996, Oncogene.

[53]  Elizabeth Yang,et al.  Serine Phosphorylation of Death Agonist BAD in Response to Survival Factor Results in Binding to 14-3-3 Not BCL-XL , 1996, Cell.

[54]  D. Haines,et al.  Expression of 14-3-3 gamma in injured arteries and growth factor- and cytokine-stimulated human vascular smooth muscle cells. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[55]  K. Uchida,et al.  Enhanced Chloride Cell Turnover in the Gills of Chum Salmon Fry in Seawater , 1996 .

[56]  B. Brenner,et al.  Transcriptional responses to tubule challenges. , 1996, Kidney International.

[57]  X. F. Zhang,et al.  Identification of the 14.3.3 ζ Domains Important for Self-association and Raf Binding (*) , 1995, The Journal of Biological Chemistry.

[58]  R. Burgoyne,et al.  Distinct effects of alpha-SNAP, 14-3-3 proteins, and calmodulin on priming and triggering of regulated exocytosis , 1995, The Journal of cell biology.

[59]  J. Rim,et al.  The MAP kinase cascade is not essential for transcriptional stimulation of osmolyte transporter genes. , 1995, Biochemical and biophysical research communications.

[60]  J. Bard,et al.  The Mouse 14-3-3 ϵ Isoform, a Kinase Regulator Whose Expression Pattern Is Modulated in Mesenchyme and Neuronal Differentiation , 1995 .

[61]  P. Kinnunen,et al.  Phospholipase A2 as a mechanosensor. , 1995, Biophysical journal.

[62]  E. Krebs,et al.  Sequential activation of Raf-1 kinase, mitogen-activated protein (MAP) kinase kinase, MAP kinase, and S6 kinase by hyperosmolality in renal cells. , 1994, The Journal of biological chemistry.

[63]  T. Tetaz,et al.  Association of a phospholipase A2 (14-3-3 protein) with the platelet glycoprotein Ib-IX complex. , 1994, The Journal of biological chemistry.

[64]  A. Yamauchi,et al.  Mitogen-activated protein kinase and its activator are regulated by hypertonic stress in Madin-Darby canine kidney cells. , 1994, The Journal of clinical investigation.

[65]  J. Dubochet,et al.  The twist, writhe and overall shape of supercoiled DNA change during counterion-induced transition from a loosely to a tightly interwound superhelix. Possible implications for DNA structure in vivo. , 1994, Journal of molecular biology.

[66]  R. Okayasu,et al.  Ionizing radiation induces two forms of interphase chromosome breaks in Chinese hamster ovary cells that rejoin with different kinetics and show different sensitivity to treatment in hypertonic medium or beta-araA. , 1993, Radiation research.

[67]  Y. Liu,et al.  Protein phosphatase type 2B (calcineurin)‐mediated, FK506‐sensitive regulation of intracellular ions in yeast is an important determinant for adaptation to high salt stress conditions. , 1993, The EMBO journal.

[68]  S. Gullans,et al.  An osmotically tolerant inner medullary collecting duct cell line from an SV40 transgenic mouse. , 1993, The American journal of physiology.

[69]  C. Beadling,et al.  Isolation of interleukin 2-induced immediate-early genes. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[70]  C. Lytle,et al.  The Na-K-Cl cotransport protein of shark rectal gland. II. Regulation by direct phosphorylation. , 1992, The Journal of biological chemistry.

[71]  C. Nowak.  Chromosomal aberrations in V79 hamster cells induced by hyperosmotic solutions of NaCl. , 1990, Mutation research.

[72]  A. Fornace,et al.  DNA damage-inducible transcripts in mammalian cells. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[73]  M. Armstrong,et al.  Effects of high osmotic strength on chromosome aberrations, sister-chromatid exchanges and DNA strand breaks, and the relation to toxicity. , 1987, Mutation research.

[74]  T. Triche,et al.  High NaCl induces stable changes in phenotype and karyotype of renal cells in culture. , 1987, American Journal of Physiology.

[75]  E. Azzam,et al.  Modification of cell survival and transformation by exposure to anisotonic solutions during irradiation. , 1985, Radiation research.

[76]  W. Bonner,et al.  Phosphorylation of histones in cells treated with hypertonic and acidic media , 1984, Molecular and cellular biology.

[77]  W. Bonner,et al.  Quantitative determination of histone modification. H2A acetylation and phosphorylation. , 1981, The Journal of biological chemistry.

[78]  P. Laurent,et al.  Morphology of gill epithelia in fish. , 1980, The American journal of physiology.

[79]  W. Williams.  WHY IS SEA-WATER SALT? , 1892, Science.

[80]  D. Kültz.  Chapter 12 – Osmotic regulation of DNA activity and the cell cycle , 2000 .

[81]  S. Masters,et al.  14-3-3 proteins: structure, function, and regulation. , 2000, Annual review of pharmacology and toxicology.

[82]  J. Taylor,et al.  Caged single and double strand breaks. , 2000, Bioconjugate chemistry.

[83]  E. Hoffmann,et al.  Sensors and signal transduction in the activation of cell volume regulatory ion transport systems. , 1998, Contributions to nephrology.

[84]  D. Kültz,et al.  Intracellular signaling in response to osmotic stress. , 1998, Contributions to nephrology.

[85]  D. Kültz,et al.  Regulation of gene expression by hypertonicity. , 1997, Annual review of physiology.

[86]  M. Tsukahara,et al.  Alteration of γ-ray-induced Chromosome Aberration by 0·5 m NaCl in Chinese Hamster Cells , 1995 .

[87]  D. Liebermann,et al.  Sequence and expression of a cDNA encoding MyD118: a novel myeloid differentiation primary response gene induced by multiple cytokines. , 1991, Oncogene.

[88]  T. Kosaka,et al.  Correlation between non-repairable DNA lesions and fixation of cell damage by hypertonic solutions in Chinese hamster cells. , 1990, International journal of radiation biology.

[89]  S. Abraham,et al.  Influence of temperature, environmental salinity and fasting on the patterns of fatty acids synthesized by gills and liver of the european eel (Anguilla anguilla). , 1983, Comparative biochemistry and physiology. B, Comparative biochemistry.

[90]  S. Abraham,et al.  The influence of environmental salinity, temperature, ionizing irradiation and yellow or silver stage on lipid metabolism in the gills of the european eel (Anguilla anguilla). , 1979, Comparative biochemistry and physiology. B, Comparative biochemistry.