© 2001 by The Society for Integrative and Comparative Biology
Osmotically Responsive Genes: The Mammalian Osmotic Response Element (ORE)1
1 Laboratory of Kidney and Electrolyte Metabolism, National Heart Lung Blood Institute, National Institutes of Health, 10 Center Dr—MSC 1603, Bethesda, Maryland 20892-1603
 |
SYNOPSIS |
|---|
TOP
 SYNOPSIS ADAPTIVE ACCUMULATION OF ORGANIC...AN OSMOTICALLY RESPONSIVE GENE,...IDENTIFICATION OF THE MINIMAL...IDENTIFICATION OF OSMOTICALLY...WHAT IS THE MECHANISM...References |
|---|
Evolutionarily, adaptation to hyperosmotic stress through accumulation of osmotically active organic solutes (organic osmolytes) is a highly conserved mechanism. Hyperosmotic accumulation of organic osmolytes is transcriptionally regulated: e.g., betaine in bacteria (e.g., Escherichia coli), glycerol in yeast (e.g., Saccharomyces cerevisiae), betaine in plants (e.g., Spinacea oleracea L.) and sorbitol, betaine, and inositol in cells of the mammalian renal medulla. Renal medullary cells, among mammalian cells, are uniquely exposed to hyperosmotic stress; in these cells, hyperosmotic stress results in accumulation of sorbitol as one of the predominant osmolytes. Sorbitol accumulates due to a rise in the synthesis rate of aldose reductase (AR), which catalyzes the conversion of glucose to sorbitol. Hyperosmotic stress increases transcription of the AR gene which leads to a rise in AR mRNA levels. In cloning and characterizing the rabbit AR gene, the first evidence of a eukaryotic osmotic response element (ORE) was found. Since then, several mammalian OREs (also called TonE) have been discovered. Sequence containing an ORE was identified for the canine Na+- and Cl–-coupled betaine transporter gene as well as the Na+/myo-inositol cotransporter gene. Because it is possible to find homology between the OREs of the AR genes and those of the betaine and inositol genes, a consensus for the mammalian ORE was derived by functional assessment. Most recent studies have resulted in the discovery of other cis-elements that potentiate the ORE response and a trans-activating factor that binds to the ORE.
|
ADAPTIVE ACCUMULATION OF ORGANIC OSMOLYTES |
|---|
|
TOP
SYNOPSISADAPTIVE ACCUMULATION OF ORGANIC...AN OSMOTICALLY RESPONSIVE GENE,...IDENTIFICATION OF THE MINIMAL...IDENTIFICATION OF OSMOTICALLY...WHAT IS THE MECHANISM...References |
|---|
Many organisms have a remarkable range of osmotic tolerance. The halobacteria have a salt requirement and a survival range between 2.8 and 6.2 M (saturated) NaCl (Brown, 1976
). Dunaliella salina, a green alga, can also tolerate saturated NaCl and media as low as 0.3 M NaCl (Brown, 1976). Marine invertebrates are variable in their abilities with some mangrove and estuarine species such as Elysia chlorotica surviving between 24 and 2,422 mosmol (Dragolovich and Pierce, 1994). While mammalian extracellular fluid is strictly regulated at about one third the salt concentration of seawater (full-strength seawater 
1,000 mosmol), cells in the kidney of virtually any mammal are routinely exposed to two- to three-fold the salinity of seawater.
A principle common to most bacteria and all eukaryotes is the adaptive accumulation of small organic compounds termed organic osmolytes in response to hyperosmotic stress. With the exception of the halobacteria which accumulate Na+ and K+, virtually all other organisms, including other bacteria, have the same adaptive response to a high salt environment. Organic osmolytes are accumulated almost universally because they, unlike equivalent concentrations of inorganic ions, do not perturb macromolecular function (Yancey et al., 1982; Yancey, 2001). While it is true that many cell types rapidly generate high concentrations of inorganic ions in response to hyperosmotic stress, this is essentially a short-term adaptation. In the long-term, the accumulated inorganic ions are replaced with organic osmolytes.
Organic osmolytes fall within relatively few categories of compounds such as amino acids and their derivatives, polyols and trimethylamines (Yancey et al., 1982; Yancey, 2001). Bacteria accumulate betaine (Lucht and Bremer, 1994), yeast and algae accumulate glycerol (Brown, 1976; Albertyn et al., 1994; Levin and Errede, 1995), plants accumulate betaine (Rhodes and Hanson, 1993), marine invertebrates and fishes accumulate mostly amino acids and trimethylamines (Yancey, 1982; Yancey, 2001), and mammalian kidney cells accumulate sorbitol, betaine, inositol, and taurine (García-Pérez and Burg, 1991).
The mechanism by which osmolytes are accumulated, during hyperosmotic stress, differs among taxonomic groups. In bacteria, betaine is transported via a system encoded by the proU operon (Lucht and Bremer, 1994; Bremer, 2001); yeast generate glycerol metabolically through glycerol-3-phosphate dehydrogenase (GPD1) (Albertyn et al., 1994). Plants synthesize betaine through the enzyme betaine aldehyde dehydrogenase (BADH) (Rhodes and Hanson, 1993) whereas sorbitol, in mammals, is generated metabolically from glucose through the enzyme aldose reductase (AR) (Bagnasco et al., 1987). Other osmolytes accumulate in mammalian renal cells through Na+ and Na+ plus Cl–-coupled transporters for betaine, inositol, and taurine (Burg et al., 1997). Regardless of the mechanism of accumulation, the critical regulatory step for each of these osmolytes is at the level of transcription of the respective gene (Rhodes and Hanson, 1993; Lucht and Bremer, 1994; Albertyn et al., 1994; Burg et al., 1997).
That the accumulation of organic osmolytes is an almost ubiquitous adaptive mechanism, that the compounds accumulated by highly diverse organisms fall into a relatively small number of classes of compounds, and that their accumulation is regulated at the transcriptional level suggest there is some highly conserved mechanism that all of these organisms have in common. Alternatively, the similarity in adaptive response is a matter of convergence. The hypothesis that there is a conserved mechanism led to the discovery of the mammalian osmotic response element (ORE) (Ferraris et al., 1994, 1996).
In the following, the adaptive accumulation of sorbitol in mammalian renal cells during hyperosmotic stress will be used as an example of the extent of current knowledge on the mammalian ORE.
|
AN OSMOTICALLY RESPONSIVE GENE, ALDOSE REDUCTASE (AR) |
|---|
|
TOP
SYNOPSISADAPTIVE ACCUMULATION OF ORGANIC...AN OSMOTICALLY RESPONSIVE GENE,...IDENTIFICATION OF THE MINIMAL...IDENTIFICATION OF OSMOTICALLY...WHAT IS THE MECHANISM...References |
|---|
In response to an increase in extracellular osmolality, sorbitol accumulates in renal cells as a result of an increase in the activity of aldose reductase (Bagnasco et al., 1987, 1988
; Uchida et al., 1989), the enzyme responsible for the conversion of glucose to sorbitol. Increased AR activity results from an increase in the amount of AR protein which, in turn, results from an increase in the rate of AR protein synthesis (Moriyama et al., 1989). The rate of AR protein synthesis increases 15-fold within 24-hr of onset of hyperosmotic stress. The degradation rate of AR is not affected by osmolality and is quite slow, with the enzyme having a half-life of about 6 days (Bedford et al., 1987; Moriyama et al., 1989).
The increase in the amount of AR protein translated is due to hyperosmotic induction of AR mRNA abundance (García-Pérez et al., 1989) which, in turn, is a function of increased transcription of the AR gene (Smardo et al., 1992). Stability of the AR mRNA is not affected by medium osmolality and hence is not responsible for the noted increase in mRNA (Smardo et al., 1992).
To determine the mechanism whereby hyperosmolality regulates transcription of the AR gene, it was necessary to clone the gene and characterize its regulatory regions. The genomic structure of human, mouse, rat, and rabbit AR is now known; regardless of species, the gene is organized into 10 exons and 9 introns and intron splice site positions are constant (Graham et al., 1991a, b; Pailhoux et al., 1992; Ferraris et al., 1994). The promoter, situated upstream (–208/+27) of the transcription start site (nucleotide = +1) has a TATA box and a CAAT box and is not responsive to osmolality (Wang et al., 1993; Ferraris et al., 1994). However, upstream of the promoter, the nucleotides –3,429/–209 of the rabbit aldose reductase gene contain one or more osmotic response elements (OREs) (Fig. 1). This was determined by the ability of nt –3,429/+27 to drive the transcription of a downstream luciferase gene in transient transfections (Ferraris et al., 1994, 1996). Relative to the promoter alone (–208/+27), the gene fragment –3,429/+27 has a hyperosmotic over isoosmotic response ratio of 9.4. By testing dozens of overlapping and progressively smaller, PCR-generated constructs (only a summary is shown in Fig. 1) the element can be narrowed down to its essential nucleotides. Unlike nested deletions, the design of this approach allows examination of all fragments of the sequence –3,429/+27, not just those that remain after deletion. From Figure 1, two observations are evident: (1) –1,170/–894 contains an independently active ORE, i.e., sequence contained within this fragment is not dependent on surrounding sequence to respond to osmolality and (2) potentiating elements might exist since the activity level of –1,170/+27 is lower than that of –3,429/+27. The latter observation parallels that seen in other cis-element studies (Takenaka et al., 1994). The fact that fragments such as –2,705/–1,152 do not show osmotic activity may merely indicate that the elements are potentiating rather than independently active.
|
|
IDENTIFICATION OF THE MINIMAL ESSENTIAL ORE AND DEFINITION OF ITS FUNCTIONAL CONSENSUS |
|---|
|
TOP
SYNOPSISADAPTIVE ACCUMULATION OF ORGANIC...AN OSMOTICALLY RESPONSIVE GENE,...IDENTIFICATION OF THE MINIMAL...IDENTIFICATION OF OSMOTICALLY...WHAT IS THE MECHANISM...References |
|---|
Continued testing of overlapping constructs results in definition of the smallest sequence capable of conferring osmotic response on a downstream gene (Ferraris et al., 1996
). When the responsive element is narrowed down to 17 bp (–1,108/–1,092), nucleotides can be eliminated in a base by base fashion (Fig. 2). At the 5' end, response is lost response when base –1,105 is removed. At the 3' end, elimination of bases does not reduce activity until removal of base –1,094 which results in equivocal response (Ferraris et al., 1996). However, if –1,094 is changed from a cytidine to an adenosine, a change that converts from a one ring structure to a two ring structure and, in terms of basepairing, from a triple bond to a double bond, full response is seen (Fig. 2). The conclusion is that eliminating position –1,094 affects osmotic response but the nucleotide does not have to be a pyrimidine. The minimal essential ORE of the rabbit AR gene has the sequence CGGAAAATCAC(C) and is defined by nucleotides –1,105/–1,094 (Ferraris et al., 1996).
|
Definition of the mammalian functional consensus is an ongoing process. If there are insufficient sequences known for independently active OREs then experimental methods need to be devised to define a functional consensus. One approach is to systematically change each base to every other possible nucleotide and test them for function in transient transfections. This was done with the rabbit ORE sequence (Ferraris et al., 1999
). The criterion for activity is based on whether a given construct significantly differs from the negative control which, in this case, is the promoter alone (response = 1.0). Constructs ranged in osmotic response from 0.8 ± 0.03 to 2.7 ± 0.27 with the positive control (native rabbit ORE) having a response of 2.2 ± 0.08. However, an additional independent assay is used on the constructs; this is the ability of a given construct to compete with the native ORE in an electophoretic mobility shift assay (EMSA). An example of this assay is shown in Figure 3. In lane 1 is the probe alone (off gel), in lane 2 is the 17 bp probe containing the native ORE plus nuclear extract from isoosmotically treated cells. In all of the rest of the lanes the nuclear extract is from hyperosmotically treated cells. Lane 3 contains no competitor and the appearance of two slowly migrating bands believed to represent binding to cognate transcription factors. Lanes 4 and 5 contain the cold native ORE as specific competitor at a 10- and 50-fold molar excess and the disappearance of the two bands. Lanes 6 and 7 and 10 and 11 contain constructs that have single base changes but effectively compete with the ORE containing probe i.e., the shifted bands disappear as in lanes 4 and 5. Lanes 8 and 9 contain a construct that has a single base change but does not compete with the ORE containing probe.
|
A summary of results of all possible single base substitutions at each nucleotide comprising the ORE is shown in Figure 4. Constructs that generate an osmotic response of 1.4 or greater also have effective binding activity in EMSAs whereas those with values of 1.3 or less do not. Values of 1.3 or less also are not different from the promoter alone in statistical analysis of transfection data (Ferraris et al., 1999
). From these data we generated the functional consensus shown as Consensus ORE (Fig. 4). That sequence is (A/C/G/T)GGAAA(A/T) (A/G/T)(A/C/T)(A/C)C(A/C/G/T) or in single letter usage NGGAAAWDHMC(N).
|
Independently active OREs or TonEs have been identified in the human and mouse AR genes, the Na+ plus Cl– coupled betaine transporter gene (BGT1), the Na+ coupled inositol transporter gene (SMIT), and upstream of an unknown human gene (designated ORE-X) (Takenaka et al., 1994
; Ruepp et al., 1996; Daoudal et al., 1997; Ko et al., 1997; Zhou and Cammarata, 1997; Rim et al., 1998). These can be used to generate a Putative Consensus (A/C/T)GGAAA(A/G)(C/G/T)(C/T)(A/C)C(A/C/T) or, in single letter terminology, HGGAAARBYMCH based on maximum homology as shown in Figure 4 (duplicate sequences from different genes are not shown). All are in agreement with the functional consensus for an independently active ORE (Ferraris et al., 1999) except three found in the SMIT gene. Two of these have a G at position –1,099 and one has a C at position –1,098 in the rabbit ORE. Since these sequences have been shown to be independently active as opposed to potentiating (Rim et al., 1998), the functional consensus should be modified to include these observations. The current consensus ORE thus is (A/C/G/T)GGAAA(A/G/T) (A/C/G/T)(A/C/T)(A/C)C(A/C/G/T) or in single letter notation NGGAAADNHMCN (Fig. 4). The fact that a G at position –1,099 or a C at position –1,098 in the rabbit ORE eliminates osmotic activity (Ferraris et al., 1999) has to be reconciled by recognition that activity of an ORE is likely to be a function of all of its nucleotides to one degree or another. The SMIT OREs are not identical to the rabbit OREs with only the exception of the two bases noted; each has between 3 and 5 other nucleotide differences. In the context of the SMIT OREs, a G at position –1,099 or a C at –1,098 is independently active.
As noted previously for the functionally derived consensus (Ferraris et al., 1999), the current functional consensus allows more latitude per position than the predicted putative consensus derived merely by maximizing the homology of presently known independently active OREs (Fig. 4).
|
IDENTIFICATION OF OSMOTICALLY RESPONSIVE POTENTIATING ELEMENTS |
|---|
|
TOP
SYNOPSISADAPTIVE ACCUMULATION OF ORGANIC...AN OSMOTICALLY RESPONSIVE GENE,...IDENTIFICATION OF THE MINIMAL...IDENTIFICATION OF OSMOTICALLY...WHAT IS THE MECHANISM...References |
|---|
It is evident from Figure 1 that construct –1,170/–894, while positive, does not have the osmotic activity of the largest 5' flanking sequence tested –3,429/–209. In searching the 5' flanking region of the AR gene for sequence containing GGAAAA, three Potentiating Elements (PE1–3) in addition to the ORE are found; one (PE1) is in the forward direction, two (PE2 and 3) are in reverse (Ko et al., 1997
; Ferraris, unpublished observations). These were targets of selective mutation (site-directed mutation of 3 essential nucleotides) either in the native gene context (Ferraris, unpublished observations) or in restriction digest fusions where native gene context and relation to promoter were not maintained (Ko et al., 1997). There is also an AP1 site just downstream of the ORE and this was also examined for contribution to osmotic response using standard transient transfections.
Mutation of PE1 or PE2 alone reduces osmotic response significantly; mutation of the ORE alone eliminates osmotic response. This suggests that PE1 and PE2 do not independently confer osmotic response. Some of these data were suggested in Figure 1 since construct –2,705/–1,152 shows no osmotic response yet it is now known that this sequence contains PE1. Mutation of the AP1 site also reduces osmotic response significantly while mutation of PE3 has no significant effect. These results (Ferraris, unpublished observations) differ somewhat from those presented by Ko et al., 1997 who found an insignificant effect of elimination of the AP1 site (versus mutation) but more importantly did not find the ORE to be independently active. Since the independent osmotic activity of the ORE has been shown many times, these discrepancies are probably due to the nature of the restriction digest fusion constructs used in the Ko et al., 1997 study. The data are consistent with the ORE as the only independently active osmotic response element in the –3,429/–209 flanking region of the rabbit AR gene. They also indicate PE1 and PE2 and the AP1 site are potentiating but are not independently active (Ferraris, unpublished observations).
The AR gene is not the only osmotically responsive gene that is controlled by multiple OREs or potentiating elements. BGT1 is controlled by two independently, but not equally, active TonEs while the SMIT gene has five (Miyakawa et al., 1999; Rim et al., 1998).
|
WHAT IS THE MECHANISM BY WHICH AN ORE ENHANCES TRANSCRIPTION OF A GENE? |
|---|
|
TOP
SYNOPSISADAPTIVE ACCUMULATION OF ORGANIC...AN OSMOTICALLY RESPONSIVE GENE,...IDENTIFICATION OF THE MINIMAL...IDENTIFICATION OF OSMOTICALLY...WHAT IS THE MECHANISM...References |
|---|
Based on the type of evidence shown in Figure 3 where there is demonstrated binding of a protein that is present in the nucleus of cells exposed to high salt compared with nuclear extracts from cells in low salt, a number of laboratories set about trying to clone this putative transcription factor. Recently, three groups have been successful in cloning the binding protein (BP) known both as OREBP and TonEBP (Miyakawa et al., 1999
; López-Rodríguez et al., 1999; Ko et al., 2000). Evidence for it being the correct protein includes: (1) overexpression of a dominant negative form of the protein (comprised of amino terminal amino acids containing the DNA binding region) in transient transfections inhibits hyperosmotic induction of transcription in ORE/TonE containing reporter constructs, (2) stable transfection of a dominant negative form of the protein reduces hyperosmotic induction of aldose reductase mRNA, and (3) electrophoretic mobility shift characteristics of the recombinant proteins match those of nuclear proteins from hyperosmotically induced cells (Miyakawa et al., 1999; Ko et al., 2000).
Data on the behavior of the protein is somewhat contradictory. There is evidence that the protein is induced under hyperosmotic conditions and that the protein is both cytoplasmic and nuclear under isoosmotic conditions but is translocated to the nucleus under hyperosmotic conditions (Miyakawa et al., 1999; Ko et al., 2000). López-Rodríguez et al., 1999, however, contend that it is a constitutively expressed nuclear phosphoprotein.
|
FOOTNOTES |
|---|
1 From the Symposium Osmoregulation: An Integrated Approach presented at the Annual Meeting of the Society for Integrative and Comparative Biology, 4–8 January 2000, at Atlanta, Georgia.
2 E-mail: jdf{at}helix.nih.gov
|
References |
|---|
|
TOP
SYNOPSISADAPTIVE ACCUMULATION OF ORGANIC...AN OSMOTICALLY RESPONSIVE GENE,...IDENTIFICATION OF THE MINIMAL...IDENTIFICATION OF OSMOTICALLY...WHAT IS THE MECHANISM...References |
|---|
Albertyn, J., S. Hohmann, J. M. Thevelein, and B. A. Prior. 1994. GPD1, which encodes glycerol-3-phosphate dehydrogenase, is essential for growth under osmotic stress in Saccharomyces cerevisiae, and its expression is regulated by the high-osmolarity glycerol response pathway. Mol. Cell. Biol, 14:4135-4144.
Bagnasco, S., S. Uchida, R. Balaban, P. Kador, and M. Burg. 1987. Induction of aldose reductase and sorbitol in renal inner medullary cells by elevated extracellular NaCl. Proc. Natl. Acad. Sci. U.S.A, 84:1718-1720.
Bagnasco, S. M., H. R. Murphy, J. J. Bedford, and M. B. Burg. 1988. Osmoregulation by slow changes in aldose reductase and rapid changes in sorbitol flux. Am. J. Physiol, 254:C788-C792.
Bedford, J. J., S. M. Bagnasco, P. F. Kador, W. H. Harris Jr.,, and M. B. Burg. 1987. Characterization and purification of a mammalian osmoregulatory protein, aldose reductase, induced in renal medullary cells by high extracellular NaCl. J. Biol. Chem, 262:14255-14259.
Brown, A. D. 1976. Microbial water stress. Bacteriological Reviews, 40:803-846.
Burg, M. B., E. D. Kwon, and D. Kültz. 1997. Regulation of gene expression by hypertonicity. Annu. Rev. Physiol, 59:437-455.[CrossRef][Web of Science][Medline]
Daoudal, S., C. Tournaire, A. Halere, G. Veyssiere, and C. Jean. 1997. Isolation of the mouse aldose reductase promoter and identification of a tonicity-responsive element. J. Biol. Chem, 272:2615-2619.
Dragolovich, J., and S. K. Pierce. 1994. The role and regulation of methylamines in the response of cells to osmotic stress. In K. Strange (ed.), Cellular and molecular physiology of cell volume regulation, pp. 123–132. CRC Press, Boca Ratan, Florida.
Ferraris, J. D., C. K. Williams, B. M. Martin, M. B. Burg, and A. García-Pérez. 1994. Cloning, genomic organization, and osmotic response of the aldose reductase gene. Proc. Natl. Acad. Sci. U.S.A, 91:10742-10746.
Ferraris, J. D., C. K. Williams, K.-Y. Jung, J. J. Bedford, M. B. Burg, and A. García-Pérez. 1996. ORE, a eukaryotic minimal essential osmotic response element. J. Biol. Chem, 271:18318-18321.
Ferraris, J. D., C. K. Williams, A. Ohtaka, and A. García-Pérez. 1999. Functional consensus for mammalian osmotic response elements. Am. J. Physiol, 276:C667-C673.
García-Pérez, A., B. Martin, H. R. Murphy, S. Uchida, H. Murer, B. D. Cowley, J. S. Handler, and M. B. Burg. 1989. Molecular cloning of cDNA coding for kidney aldose reductase: Regulation of specific mRNA accumulation by NaCl-mediated osmotic stress. J. Biol. Chem, 264:16815-16821.
García-Pérez, A., and M. B. Burg. 1991. Renal medullary organic osmolytes. Physiol. Rev, 71:1081-1115.
Graham, A., L. Brown, P. J. Hedge, A. J. Gammack, and A. F. Markham. 1991a.. Structure of the human aldose reductase gene. J. Biol. Chem, 266:6872-6877.
Graham, C., C. Szpirer, G. Levan, and D. Carper. 1991b.. Characterization of the aldose reductase-encoding gene family in rat. Gene, 107:259-267.[CrossRef][Web of Science][Medline]
Ko, B. C. B., B. Ruepp, K. M. Bohren, K. H. Gabbay, and S. M. Chung. 1997. Identification and characterization of multiple osmotic response sequences in the human aldose reductase gene. J. Biol. Chem, 272:16431-16437.
Ko, B. C. B., C. W. Turck, K. W. Y. Lee, Y. Yang, and S. M. Chung. 2000. Purification, identification, and characterization of an osmotic response element binding protein. Biochem. Biophys. Res. Comm, 270:52-61.[CrossRef][Web of Science][Medline]
Levin, D. E., and B. Errede. 1995. The proliferation of MAP kinase signaling pathways in yeast. Curr. Opin. Cell Biol, 7:197-202.[CrossRef][Web of Science][Medline]
Lopez-Rodríguez, C., J. Aramburu, A. S. Rakeman, and A. Rao. 1999. NFAT5, a constitutively nuclear NFAT protein that does not cooperate with Fos and Jun. Proc. Natl. Acad. Sci. U.S.A, 96:7214-7219.
Lucht, J. M., and E. Bremer. 1994. Adaptation of Escherichia coli to high osmolarity environments: Osmoregulation of the high-affinity glycine betaine transport system ProU. FEMS Microbiol. Rev, 14:3-20.[CrossRef][Web of Science][Medline]
Miyakawa, H., J. S. Rim, J. S. Handler, and H. M. Kwon. 1999. Identification of the second tonicity-responsive enhancer for the betaine transporter (BGT1) gene. Biochimica et Biophysica Acta, 1446:359-364.[Medline]
Moriyama, T., A. García-Pérez, and M. B. Burg. 1989. Osmotic regulation of aldose reductase protein synthesis in renal medullary cells. J. Biol. Chem, 264:16810-16814.
Pailhoux, E., G. Veyssiere, S. Fabre, C. Tournaire, and C. Jean. 1992. The genomic organization and DNA sequence of the mouse vas deferens androgen-regulated protein gene. J. Steroid Biochem. Mol. Biol, 42:561-568.[CrossRef][Web of Science][Medline]
Rhodes, D., and A. D. Hanson. 1993. Quaternary ammonium and tertiary sulfonium compounds in higher plants. Annual Rev. Plant Physiol. Plant Mol. Biol, 44:357-384.
Ruepp, B., K. M. Bohren, and K. H. Gabbay. 1996. Characterization of the osmotic response element of the human aldose reductase gene promoter. Proc. Natl. Acad. Sci. U.S.A, 93:8624-8629.
Rim, J. S., M. G. Atta, S. C. Dahl, G. T. Berry, J. S. Handler, and H. M. Kwon. 1998. Transcription of the sodium/myo-inositol cotransporter gene is regulated by multiple tonicity-responsive enhancers spread over 50 kilobase pairs in the 5'-flanking region. J. Biol. Chem, 273:20615-20621.
Smardo, F., M. B. Burg, and A. García-Pérez. 1992. Kidney aldose reductase gene transcription is osmotically regulated. Am. J. Physiol, 262:C776-C782.
Takenaka, M., A. Preston, H. Kwon, and J. S. Handler. 1994. The tonicity-sensitive element that mediates increased transcription of the betaine transporter gene in response to hypertonic stress. J. Biol. Chem, 269:29379-29381.
Uchida, S., A. García-Pérez, H. R. Murphy, and M. B. Burg. 1989. Signal for induction of aldose reductase in renal medullary cells by high external NaCl. Am. J. Physiol, 256:C614-C620.
Wang, K., K. Bohren, and K. Gabbay. 1993. Characterization of the human aldose reductase gene promoter. J. Biol. Chem, 268:16052-16058.
Yancey, P. H. 2001. Water stress, osmolytes and proteins. Amer. Zool, 41:699-709.[CrossRef]
Yancey, P., M. Clark, S. Hand, R. Bowlus, and G. Somero. 1982. Living with water stress: Evolution of osmolyte systems. Science, 217:1214-1222.
Zhou, C., and P. R. Cammarata. 1997. Cloning the bovine Na+/myo-inositol cotransporter gene and characterization of an osmotic responsive promoter. Exp. Eye Res, 35:349-363.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||