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Russell W. Chesney - One of the best experts on this subject based on the ideXlab platform.
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The Taurine Transporter: mechanisms of regulation.
Acta physiologica (Oxford England), 2006Co-Authors: Xiaobin Han, Andrea Budreau Patters, Deborah P. Jones, I. Zelikovic, Russell W. ChesneyAbstract:Taurine transport undergoes an adaptive response to changes in Taurine availability. Unlike most amino acids, Taurine is not metabolized or incorporated into protein but remains free in the intracellular water. Most amino acids are reabsorbed at rates of 98-99%, but reabsorption of Taurine may range from 40% to 99.5%. Factors that influence Taurine accumulation include ionic environment, electrochemical charge, and post-translational and transcriptional factors. Among these are protein kinase C (PKC) activation and transactivation or repression by proto-oncogenes such as WT1, c-Jun, c-Myb and p53. Renal adaptive regulation of the Taurine Transporter (TauT) was studied in vivo and in vitro. Site-directed mutagenesis and the oocyte expression system were used to study post-translational regulation of the TauT by PKC. Reporter genes and Northern and Western blots were used to study transcriptional regulation of the Taurine Transporter gene (TauT). We demonstrated that (i) the body pool of Taurine is controlled through renal adaptive regulation of TauT in response to Taurine availability; (ii) ionic environment, electrochemical charge, pH, and developmental ontogeny influence renal Taurine accumulation; (iii) the fourth segment of TauT is involved in the gating of Taurine across the cell membrane, which is controlled by PKC phosphorylation of serine 322 at the post-translational level; (iv) expression of TauT is repressed by the p53 tumour suppressor gene and is transactivated by proto-oncogenes such as WT1, c-Jun, and c-Myb; and (v) over-expression of TauT protects renal cells from cisplatin-induced nephrotoxicity.
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Regulation of Taurine Transporter gene (TauT) by WT1.
FEBS letters, 2003Co-Authors: Xiaobin Han, Russell W. ChesneyAbstract:In the present study we have demonstrated that WT1 (Wilms tumor suppressor gene) enhances the expression of TauT (Taurine Transporter gene) in human embryonic kidney 293 cells in a dose-dependent manner. TauT promoter activity was increased five-fold by cotransfection of a full-length TauT promoter-reporter construct with WT1. Electrophoretic mobility shift assays (EMSAs) using nuclear extracts from WT1-overexpressing 293 cells showed a putative WT1-binding site in the basal promoter region of TauT, which bound to WT1 in EMSAs. Mutation of this WT1 consensus sequence abolished binding of WT1. These results demonstrate that TauT may represent a downstream target gene of WT1 during renal development.
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Transcriptional Repression of Taurine Transporter Gene (TauT) by p53 in Renal Cells
The Journal of biological chemistry, 2002Co-Authors: Xiaobin Han, Andrea Budreau Patters, Russell W. ChesneyAbstract:Abstract Taurine, an intracellular osmolyte whose body pool size is adaptively regulated by the kidney, is required for normal renal development. Overexpression of the p53 tumor suppressor gene in p53 transgenic mice results in renal malformation, suggesting that altered expression of certain p53 target gene(s) involved in renal development may be responsible. This study shows that the Taurine Transporter gene (TauT) is a transcriptional target of p53. Expression of TauT was decreased after activation of p53 by doxorubicin, a DNA-damaging drug, in 293 and NRK-52E renal cells.TauT promoter activity was decreased 5–10-fold by cotransfection of a full-length TauT promoter-reporter construct with p53, which was reversed by cotransfection with a mutant p53 (p53-281). Electrophoretic mobility shift assays using nuclear extracts from p53-expressing (10)1val cells showed a putative p53-binding site in the TauT promoter region, which bound to the p53 in electrophoretic mobility shift assays. Mutation of this p53 consensus sequence abolished binding of p53. These results demonstrate that TauT may represent a downstream target gene of p53 that could link the roles of p53 in renal development and apoptosis.
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The Taurine Transporter gene and its role in renal development.
Amino Acids, 2000Co-Authors: Xiaobin Han, Andrea M. Budreau, Russell W. ChesneyAbstract:This paper examines a unique hypothesis regarding an important role for Taurine in renal development. Taurine-deficient neonatal kittens show renal developmental abnormalities, one of several lines of support for this speculation. Adaptive regulation of the Taurine Transporter gene is critical in mammalian species because maintenance of adequate tissue levels of Taurine is essential to the normal development of the retina and the central nervous system. Observations of the remarkable phenotypic similarity that exists between children with deletion of bands p25-pter of chromosome 3 and Taurine-deficient kits led us to hypothesize that deletion of the renal Taurine Transporter gene (TauT) might contribute to some features of the 3p-syndrome. Further, the renal Taurine Transporter gene is down-regulated by the tumor suppressor gene p53, and up-regulated by the Wilms tumor (WT-1) and early growth response-1 (EGR-1) genes. It has been demonstrated using WT-1 gene knockout mice that WT-1 is critical for normal renal development. In contrast, transgenic mice overexpressing the p53 gene have renal development defects, including hypoplasia similar to that observed in the Taurine-deficient kitten. This paper reviews evidence that altered expression of the renal Taurine Transporter may result in reduced intracellular Taurine content, which in turn may lead to abnormal cell volume regulation, cell death and, ultimately, defective renal development.
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Molecular Cloning of Promoter Region of Taurine Transporter Gene That Is Regulated by p53 Tumor Suppressor Gene
Pediatric Research, 1999Co-Authors: Andrea M. Budreau, Russell W. ChesneyAbstract:Molecular Cloning of Promoter Region of Taurine Transporter Gene That Is Regulated by p53 Tumor Suppressor Gene
Xiaobin Han - One of the best experts on this subject based on the ideXlab platform.
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The Taurine Transporter: mechanisms of regulation.
Acta physiologica (Oxford England), 2006Co-Authors: Xiaobin Han, Andrea Budreau Patters, Deborah P. Jones, I. Zelikovic, Russell W. ChesneyAbstract:Taurine transport undergoes an adaptive response to changes in Taurine availability. Unlike most amino acids, Taurine is not metabolized or incorporated into protein but remains free in the intracellular water. Most amino acids are reabsorbed at rates of 98-99%, but reabsorption of Taurine may range from 40% to 99.5%. Factors that influence Taurine accumulation include ionic environment, electrochemical charge, and post-translational and transcriptional factors. Among these are protein kinase C (PKC) activation and transactivation or repression by proto-oncogenes such as WT1, c-Jun, c-Myb and p53. Renal adaptive regulation of the Taurine Transporter (TauT) was studied in vivo and in vitro. Site-directed mutagenesis and the oocyte expression system were used to study post-translational regulation of the TauT by PKC. Reporter genes and Northern and Western blots were used to study transcriptional regulation of the Taurine Transporter gene (TauT). We demonstrated that (i) the body pool of Taurine is controlled through renal adaptive regulation of TauT in response to Taurine availability; (ii) ionic environment, electrochemical charge, pH, and developmental ontogeny influence renal Taurine accumulation; (iii) the fourth segment of TauT is involved in the gating of Taurine across the cell membrane, which is controlled by PKC phosphorylation of serine 322 at the post-translational level; (iv) expression of TauT is repressed by the p53 tumour suppressor gene and is transactivated by proto-oncogenes such as WT1, c-Jun, and c-Myb; and (v) over-expression of TauT protects renal cells from cisplatin-induced nephrotoxicity.
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Regulation of Taurine Transporter gene (TauT) by WT1.
FEBS letters, 2003Co-Authors: Xiaobin Han, Russell W. ChesneyAbstract:In the present study we have demonstrated that WT1 (Wilms tumor suppressor gene) enhances the expression of TauT (Taurine Transporter gene) in human embryonic kidney 293 cells in a dose-dependent manner. TauT promoter activity was increased five-fold by cotransfection of a full-length TauT promoter-reporter construct with WT1. Electrophoretic mobility shift assays (EMSAs) using nuclear extracts from WT1-overexpressing 293 cells showed a putative WT1-binding site in the basal promoter region of TauT, which bound to WT1 in EMSAs. Mutation of this WT1 consensus sequence abolished binding of WT1. These results demonstrate that TauT may represent a downstream target gene of WT1 during renal development.
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Transcriptional Repression of Taurine Transporter Gene (TauT) by p53 in Renal Cells
The Journal of biological chemistry, 2002Co-Authors: Xiaobin Han, Andrea Budreau Patters, Russell W. ChesneyAbstract:Abstract Taurine, an intracellular osmolyte whose body pool size is adaptively regulated by the kidney, is required for normal renal development. Overexpression of the p53 tumor suppressor gene in p53 transgenic mice results in renal malformation, suggesting that altered expression of certain p53 target gene(s) involved in renal development may be responsible. This study shows that the Taurine Transporter gene (TauT) is a transcriptional target of p53. Expression of TauT was decreased after activation of p53 by doxorubicin, a DNA-damaging drug, in 293 and NRK-52E renal cells.TauT promoter activity was decreased 5–10-fold by cotransfection of a full-length TauT promoter-reporter construct with p53, which was reversed by cotransfection with a mutant p53 (p53-281). Electrophoretic mobility shift assays using nuclear extracts from p53-expressing (10)1val cells showed a putative p53-binding site in the TauT promoter region, which bound to the p53 in electrophoretic mobility shift assays. Mutation of this p53 consensus sequence abolished binding of p53. These results demonstrate that TauT may represent a downstream target gene of p53 that could link the roles of p53 in renal development and apoptosis.
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The Taurine Transporter gene and its role in renal development.
Amino Acids, 2000Co-Authors: Xiaobin Han, Andrea M. Budreau, Russell W. ChesneyAbstract:This paper examines a unique hypothesis regarding an important role for Taurine in renal development. Taurine-deficient neonatal kittens show renal developmental abnormalities, one of several lines of support for this speculation. Adaptive regulation of the Taurine Transporter gene is critical in mammalian species because maintenance of adequate tissue levels of Taurine is essential to the normal development of the retina and the central nervous system. Observations of the remarkable phenotypic similarity that exists between children with deletion of bands p25-pter of chromosome 3 and Taurine-deficient kits led us to hypothesize that deletion of the renal Taurine Transporter gene (TauT) might contribute to some features of the 3p-syndrome. Further, the renal Taurine Transporter gene is down-regulated by the tumor suppressor gene p53, and up-regulated by the Wilms tumor (WT-1) and early growth response-1 (EGR-1) genes. It has been demonstrated using WT-1 gene knockout mice that WT-1 is critical for normal renal development. In contrast, transgenic mice overexpressing the p53 gene have renal development defects, including hypoplasia similar to that observed in the Taurine-deficient kitten. This paper reviews evidence that altered expression of the renal Taurine Transporter may result in reduced intracellular Taurine content, which in turn may lead to abnormal cell volume regulation, cell death and, ultimately, defective renal development.
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Ser-322 is a critical site for PKC regulation of the MDCK cell Taurine Transporter (pNCT)
Journal of the American Society of Nephrology : JASN, 1999Co-Authors: Xiaobin Han, Andrea M. Budreau, Russell W. ChesneyAbstract:Previous studies have shown that the Madin-Darby canine kidney cell Taurine Transporter (pNCT) is downregulated by protein kinase C (PKC) activation. In this study, it is hypothesized that the highly conserved serine-322 (Ser-322) located in the fourth intracellular segment (S4) may play an important role in the function of Taurine Transporter, which is modulated by PKC phosphorylation. It is demonstrated that Ser-322 is the critical site of PKC phosphorylation, as determined by site-directed mutagenesis. When Ser-322 of pNCT was changed to alanine (S322A) and this mutant was evaluated in an oocyte expression system, Taurine transport activity increased threefold compared with control (wild-type pNCT). Activation of PKC by the active phorbol ester 12-myristate 13-acetate did not influence Taurine transport by mutant S322A. Kinetic analysis showed that the mutation of Ser-322 essentially changed the Vmax, rather than the Km, of the Transporter. Mutation of all other PKC consensus sites did not affect Transporter activity when expressed in the oocyte system. Western blot analysis showed that expression of Taurine Transporter protein was similar in oocytes injected with either wild-type or mutant pNCT cRNA, indicating that the enhanced Taurine transport activity by mutant S322A was not caused by a greater amount of Transporter expressed in the oocyte. Furthermore, this study demonstrated that the Taurine Transporter was phosphorylated after PKC activation, and this effect was not observed in mutant S322A. In conclusion, Ser-322 is critical in PKC regulation of Taurine Transporter activity. The steady-state Taurine Transporter activity is tightly controlled by endogenous PKC phosphorylation of Ser-322, which is located in the fourth intracellular segment of the Taurine Transporter.
Andrea M. Budreau - One of the best experts on this subject based on the ideXlab platform.
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The Taurine Transporter gene and its role in renal development.
Amino Acids, 2000Co-Authors: Xiaobin Han, Andrea M. Budreau, Russell W. ChesneyAbstract:This paper examines a unique hypothesis regarding an important role for Taurine in renal development. Taurine-deficient neonatal kittens show renal developmental abnormalities, one of several lines of support for this speculation. Adaptive regulation of the Taurine Transporter gene is critical in mammalian species because maintenance of adequate tissue levels of Taurine is essential to the normal development of the retina and the central nervous system. Observations of the remarkable phenotypic similarity that exists between children with deletion of bands p25-pter of chromosome 3 and Taurine-deficient kits led us to hypothesize that deletion of the renal Taurine Transporter gene (TauT) might contribute to some features of the 3p-syndrome. Further, the renal Taurine Transporter gene is down-regulated by the tumor suppressor gene p53, and up-regulated by the Wilms tumor (WT-1) and early growth response-1 (EGR-1) genes. It has been demonstrated using WT-1 gene knockout mice that WT-1 is critical for normal renal development. In contrast, transgenic mice overexpressing the p53 gene have renal development defects, including hypoplasia similar to that observed in the Taurine-deficient kitten. This paper reviews evidence that altered expression of the renal Taurine Transporter may result in reduced intracellular Taurine content, which in turn may lead to abnormal cell volume regulation, cell death and, ultimately, defective renal development.
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Molecular Cloning of Promoter Region of Taurine Transporter Gene That Is Regulated by p53 Tumor Suppressor Gene
Pediatric Research, 1999Co-Authors: Andrea M. Budreau, Russell W. ChesneyAbstract:Molecular Cloning of Promoter Region of Taurine Transporter Gene That Is Regulated by p53 Tumor Suppressor Gene
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Ser-322 is a critical site for PKC regulation of the MDCK cell Taurine Transporter (pNCT)
Journal of the American Society of Nephrology : JASN, 1999Co-Authors: Xiaobin Han, Andrea M. Budreau, Russell W. ChesneyAbstract:Previous studies have shown that the Madin-Darby canine kidney cell Taurine Transporter (pNCT) is downregulated by protein kinase C (PKC) activation. In this study, it is hypothesized that the highly conserved serine-322 (Ser-322) located in the fourth intracellular segment (S4) may play an important role in the function of Taurine Transporter, which is modulated by PKC phosphorylation. It is demonstrated that Ser-322 is the critical site of PKC phosphorylation, as determined by site-directed mutagenesis. When Ser-322 of pNCT was changed to alanine (S322A) and this mutant was evaluated in an oocyte expression system, Taurine transport activity increased threefold compared with control (wild-type pNCT). Activation of PKC by the active phorbol ester 12-myristate 13-acetate did not influence Taurine transport by mutant S322A. Kinetic analysis showed that the mutation of Ser-322 essentially changed the Vmax, rather than the Km, of the Transporter. Mutation of all other PKC consensus sites did not affect Transporter activity when expressed in the oocyte system. Western blot analysis showed that expression of Taurine Transporter protein was similar in oocytes injected with either wild-type or mutant pNCT cRNA, indicating that the enhanced Taurine transport activity by mutant S322A was not caused by a greater amount of Transporter expressed in the oocyte. Furthermore, this study demonstrated that the Taurine Transporter was phosphorylated after PKC activation, and this effect was not observed in mutant S322A. In conclusion, Ser-322 is critical in PKC regulation of Taurine Transporter activity. The steady-state Taurine Transporter activity is tightly controlled by endogenous PKC phosphorylation of Ser-322, which is located in the fourth intracellular segment of the Taurine Transporter.
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Cloning and Characterization of the Promoter Region of the Rat Taurine Transporter Gene: Transcriptional Regulation by Taurine and Estradiol 1809
Pediatric Research, 1998Co-Authors: Xiaobin Han, Andrea M. Budreau, Russell W. ChesneyAbstract:Expression of the renal Taurine Transporter gene is regulated by intracellular Taurine content. In certain cell lines, transcription is regulated by Taurine availability. We attempted to define the nature of the signal for this adaptive response. A clone containing a segment of the 5′- upstream region of rat Taurine Transporter genomic DNA was obtained by screening a P1 library using PCR probes derived from rat brain Taurine Transporter cDNA (rB16a). The DNA (≈1.6 kb pairs) was isolated and characterized. The 5′-flanking region of the gene contains typical eukaryotic promoter elements, including a TATA box, four consensus binding sites for SP1, and two estrogen receptor half-site sequences (AGGTCA). The DNA fragment was also analyzed by transient transfection. When linke to a firefly luciferase reporter gene, it enhanced transcription 100-fold in two renal cell lines, and was influenced by the presence or absence of Taurine. Promoter activity was also enhanced by treatment with β-17 estradiol in human breast cancer cells, and in rat cardiomyocytes, but not in renal cells.
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Molecular cloning and functional expression of an LLC-PK1 cell Taurine Transporter that is adaptively regulated by Taurine.
Advances in experimental medicine and biology, 1998Co-Authors: Xiaobin Han, Andrea M. Budreau, Russell W. ChesneyAbstract:Studies have shown that the renal tubular epithelium adapts to alterations in the sulfur amino acid composition of the diet. The renal adaptive response has been described in man, mouse, rat, dog, and pig. The observed phenomenon involves increased or decreased initial rate activity of the NaCl-dependent Taurine Transporter at the brush border membrane surface of the proximal tubule following dietary manipulation of Taurine. A cDNA encoding a Taurine Transporter has been isolated from LLC-PK1 cells, designated pTAUT, and its functional properties have been examined in Xenopus laevis oocytes. The nucleotide sequence of the clone predicts a 621-amino acid protein with about 90% homology to other cloned Taurine Transporter cDNAs. When expressed in oocytes the Transporter displays a Km of 25 μM and is dependent on the presence of external sodium and chloride, characteristics similar to Taurine uptake by LLC-PK1 cells. The abundance of pTAUT mRNA and protein were up-regulated in cells cultured in Taurine-free medium as compared with cells cultured in medium containing 500 μM Taurine. Activation of PKC by PMA had no effect on adaptive regulation of pTAUT mRNA and protein, indicating that down-regulation of LLC-PK1 cell Taurine transport activity by PMA occurs at the post-translational level.
Dieter Häussinger - One of the best experts on this subject based on the ideXlab platform.
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Taurine Transporter taut deficiency impairs ammonia detoxification in mouse liver
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Natalia Qvartskhava, Boris Görg, Tobias Buschmann, Ute Albrecht, J G Bode, Niloufar Monhasery, Jessica Oenarto, Hans J Bidmon, Dieter HäussingerAbstract:Hepatic ammonia handling was analyzed in Taurine Transporter (TauT) KO mice. Surprisingly, hyperammonemia was present at an age of 3 and 12 months despite normal tissue integrity. This was accompanied by cerebral RNA oxidation. As shown in liver perfusion experiments, glutamine production from ammonia was diminished in TauT KO mice, whereas urea production was not affected. In livers from 3-month-old TauT KO mice protein expression and activity of glutamine synthetase (GS) were unaffected, whereas the ammonia-transporting RhBG protein was down-regulated by about 50%. Double reciprocal plot analysis of glutamine synthesis versus perivenous ammonia concentration revealed that TauT KO had no effect on the capacity of glutamine formation in 3-month-old mice, but doubled the ammonia concentration required for half-maximal glutamine synthesis. Since hepatic RhBG expression is restricted to GS-expressing hepatocytes, the findings suggest that an impaired ammonia transport into these cells impairs glutamine synthesis. In livers from 12-, but not 3-month-old TauT KO mice, RhBG expression was not affected, surrogate markers for oxidative stress were strongly up-regulated, and GS activity was decreased by 40% due to an inactivating tyrosine nitration. This was also reflected by kinetic analyses in perfused liver, which showed a decreased glutamine synthesizing capacity by 43% and a largely unaffected ammonia concentration dependence. It is concluded that TauT deficiency triggers hyperammonemia through impaired hepatic glutamine synthesis due to an impaired ammonia transport via RhBG at 3 months and a tyrosine nitration-dependent inactivation of GS in 12-month-old TauT KO mice.
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Loss of ability to self-heal malaria upon Taurine Transporter deletion.
Infection and immunity, 2010Co-Authors: Denis Delic, Ulrich Warskulat, Elena Borsch, Dieter Häussinger, Saad Al-qahtani, Saleh A. Alquraishi, Frank WunderlichAbstract:Deletion of the Taurine Transporter gene (taut) results in lowered levels of Taurine, the most abundant amino acid in mammals. Here, we show that taut−/− mice have lost their ability to self-heal blood-stage infections with Plasmodium chabaudi malaria. All taut−/− mice succumb to infections during crisis, while about 90% of the control taut+/+ mice survive. The latter retain unchanged Taurine levels even at peak parasitemia. Deletion of taut, however, results in the lowering of circulating Taurine levels from 540 to 264 μmol/liter, and infections cause additional lowering to 192 μmol/liter. Peak parasitemia levels in taut−/− mice are approximately 60% higher than those in taut+/+ mice, an elevation that is associated with increased systemic tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) levels, as well as with liver injuries. The latter manifest as increased systemic ammonia levels, a perturbed capacity to entrap injected particles, and increased expression of genes encoding TNF-α, IL-1β, IL-6, inducible nitric oxide synthase (iNOS), NF-κB, and vitamin D receptor (VDR). Autopsy reveals multiorgan failure as the cause of death for malaria-infected taut−/− mice. Our data indicate that taut-controlled Taurine homeostasis is essential for resistance to P. chabaudi malaria. Taurine deficiency due to taut deletion, however, impairs the eryptosis of P. chabaudi-parasitized erythrocytes and expedites increases in systemic TNF-α, IL-1β, and ammonia levels, presumably contributing to multiorgan failure in P. chabaudi-infected taut−/− mice.
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Taurine deficiency and apoptosis: findings from the Taurine Transporter knockout mouse.
Archives of biochemistry and biophysics, 2007Co-Authors: Ulrich Warskulat, Elena Borsch, Roland Reinehr, Birgit Heller-stilb, Christian Roth, Martin Witt, Dieter HäussingerAbstract:Abstract Apoptosis is characterized by cell shrinkage, nuclear condensation, DNA-fragmentation and apoptotic body formation. Compatible organic osmolytes, e.g. Taurine, modulate the cellular response to anisotonicity and may protect from apoptosis. Taurine Transporter knockout mice (taut−/− mice) show strongly decreased Taurine levels in a variety of tissues. They develop clinically important age-dependent diseases and some of them are characterized by apoptosis. Increased photoreceptor apoptosis leads to blindness of taut−/− mice at an early age. The Taurine Transporter may not be essential for the differentiation of photoreceptor cells, but many mature cells do not survive without an intact Taurine Transporter. The olfactory epithelium of taut−/− mice also exhibits structural and functional abnormalities. When compared with wild-types, taut−/− mice have a significantly higher proliferative activity of immature olfactory receptor neurons and an increased number of apoptotic cells. This is accompanied by electrophysiological findings indicating a reduced olfactory sensitivity. Furthermore, taut−/− and taut+/− mice develop moderate unspecific hepatitis and liver fibrosis beyond 1 year of age where hepatocyte apoptosis and activation of the CD95 system are pronounced.
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Phenotype of the Taurine Transporter knockout mouse.
Methods in enzymology, 2007Co-Authors: Ulrich Warskulat, Birgit Heller-stilb, Evelyn Oermann, Karl Zilles, Helmut L. Haas, Florian Lang, Dieter HäussingerAbstract:This chapter reports present knowledge on the properties of mice with disrupted gene coding for the Taurine Transporter (taut-/- mice). Study of those mice unraveled some of the roles of Taurine and its membrane transport for the development and maintenance of normal organ functions and morphology. When compared with wild-type controls, taut-/- mice have decreased Taurine levels in skeletal and heart muscle by about 98%, in brain, kidney, plasma, and retina by 80 to 90%, and in liver by about 70%. taut-/- mice exhibit a lower body mass as well as a strongly reduced exercise capacity compared with taut+/- and wild-type mice. Furthermore, taut-/- mice show a variety of pathological features, for example, subtle derangement of renal osmoregulation, changes in neuroreceptor expression, and loss of long-term potentiation in the striatum, and they develop clinically relevant age-dependent disorders, for example, visual, auditory, and olfactory dysfunctions, unspecific hepatitis, and liver fibrosis. Taurine-deficient animal models such as acutely dietary-manipulated foxes and cats, pharmacologically induced Taurine-deficient rats, and Taurine Transporter knockout mouse are powerful tools allowing identification of the mechanisms and complexities of diseases mediated by impaired Taurine transport and Taurine depletion (Chapman et al., 1993; Heller-Stilb et al., 2002; Huxtable, 1992; Lake, 1993; Moise et al., 1991; Novotny et al., 1991; Pion et al., 1987; Timbrell et al., 1995; Warskulat et al., 2004, 2006b). Taurine, which is the most abundant amino acid in many tissues, is normally found in intracellular concentrations of 10 to 70 mmol/kg in mammalian heart, brain, skeletal muscle, liver, and retina (Chapman et al., 1993; Green et al., 1991; Huxable, 1992; Timbrell et al., 1995). These high Taurine levels are maintained by an ubiquitous expression of Na(+)-dependent Taurine Transporter (TAUT) in the plasma membrane (Burg, 1995; Kwon and Handler, 1995; Lang et al., 1998; Liu et al., 1992; Ramamoorthy et al., 1994; Schloss et al., 1994; Smith et al., 1992; Uchida et al., 1992; Vinnakota et al., 1997; Yancey et al., 1975). Taurine is not incorporated into proteins. It is involved in cell volume regulation, neuromodulation, antioxidant defense, protein stabilization, stress responses, and via formation of Taurine-chloramine in immunomodulation (Chapman et al., 1993; Green et al., 1991; Huxtable, 1992; Timbrell et al., 1995). On the basis of its functions, Taurine may protect cells against various types of injury (Chapman et al., 1993; Green et al., 1991; Huxtable, 1992; Kurz et al., 1998; Park et al., 1995; Stapleton et al., 1998; Timbrell et al., 1995; Welch and Brown, 1996; Wettstein and Haussinger, 1997). In order to examine the multiple Taurine functions, murine models have several intrinsic advantages for in vivo research compared to other animal models, including lower cost, maintenance, and rapid reproduction rate. Further, experimental reagents for cellular and molecular studies are widely available for the mouse. In particular, mice can be easily genetically manipulated by making transgene and knockout mice. This chapter focuses on the phenotype of the TAUT-deficient murine model (taut-/-; Heller-Stilb et al., 2002), which may help researchers elucidate the diverse roles of Taurine in development and maintenance of normal organ functions and morphology.
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Taurine-Transporter gene knockout-induced changes in GABA_A, kainate and AMPA but not NMDA receptor binding in mouse brain
Anatomy and Embryology, 2005Co-Authors: Evelyn Oermann, Ulrich Warskulat, Birgit Heller-stilb, Dieter Häussinger, Karl ZillesAbstract:The aim of this study was to determine whether the knockout of the Taurine-Transporter gene in the mouse affects the densities of GABA_A, kainate, AMPA and NMDA receptors in the brain. The caudate-putamen, the hippocampus and its subregions, and the cerebellum of six homozygous Taurine-Transporter gene knockout mice and six wild-type (WT) animals were examined by means of quantitative receptor autoradiography. Saturation studies were carried out for all four receptor types in order to find possible intergroup differences in B _max and K _D values. Taurine-Transporter gene knockout animals showed significantly higher GABA_A receptor densities in the molecular layer of the hippocampal dentate gyrus and in the cerebellum than did WT animals. The densities of kainate receptors were significantly higher in the caudate-putamen, the CA1 and hilus regions of the hippocampus and in the cerebellum of knockout animals. The caudate-putamen and cerebellum of these mice also contained significantly higher AMPA receptor densities. However, there were no significant differences between knockout and WT animals concerning the densities of NMDA receptors. Reduced brain Taurine levels are associated with increased GABA_A, kainate and AMPA receptor densities in some of the regions we examined.
Junichi Azuma - One of the best experts on this subject based on the ideXlab platform.
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Potential Anti-aging Role of Taurine via Proper Protein Folding: A Study from Taurine Transporter Knockout Mouse
Advances in experimental medicine and biology, 2015Co-Authors: Takashi Ito, Stephen W. Schaffer, Natsuko Miyazaki, Junichi AzumaAbstract:Taurine is effective to several aging-related diseases. Taurine mediates a variety of biological actions, including osmoregulation and protein folding, which may contribute to its anti-aging role. Recent studies have proposed that the decline of protein homeostasis with advancing age leads to several aging-related disorders. Therefore, it is possible that the contribution of Taurine to proper protein folding may be associated with the effectiveness against aging-related diseases. Meanwhile, Evidence accumulating from the studies with Taurine Transporter knockout (TauTKO) mouse has indicated that tissue Taurine depletion led to aging-associated disorders in several tissues, including heart, skeletal muscle, liver, skin, and shortened the lifespan. Moreover, muscle Taurine depletion causes ER stress to activate unfolded protein response. In conclusion, endogenous Taurine acts as an anti-aging molecule via, in part, proper protein folding property.
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Cardiac and skeletal muscle abnormality in Taurine Transporter-knockout mice.
Journal of biomedical science, 2010Co-Authors: Takashi Ito, Stephen W. Schaffer, Shohei Oishi, Mika Takai, Yasushi Kimura, Yoriko Uozumi, Yasushi Fujio, Junichi AzumaAbstract:Taurine, a sulfur-containing beta-amino acid, is highly contained in heart and skeletal muscle. Taurine has a variety of biological actions, such as ion movement, calcium handling and cytoprotection in the cardiac and skeletal muscles. Meanwhile, Taurine deficiency leads various pathologies, including dilated cardiomyopathy, in cat and fox. However, the essential role of Taurine depletion on pathogenesis has not been fully clarified. To address the physiological role of Taurine in mammalian tissues, Taurine Transporter-(TauT-) knockout models were recently generated. TauTKO mice exhibited loss of body weight, abnormal cardiac function and the reduced exercise capacity with tissue Taurine depletion. In this chapter, we summarize pathological profile and histological feature of heart and skeletal muscle in TauTKO mice.
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Cardiac and skeletal muscle abnormality in Taurine Transporter-knockout mice
Journal of Biomedical Science, 2010Co-Authors: Takashi Ito, Stephen W. Schaffer, Shohei Oishi, Mika Takai, Yasushi Kimura, Yoriko Uozumi, Yasushi Fujio, Junichi AzumaAbstract:Taurine, a sulfur-containing β-amino acid, is highly contained in heart and skeletal muscle. Taurine has a variety of biological actions, such as ion movement, calcium handling and cytoprotection in the cardiac and skeletal muscles. Meanwhile, Taurine deficiency leads various pathologies, including dilated cardiomyopathy, in cat and fox. However, the essential role of Taurine depletion on pathogenesis has not been fully clarified. To address the physiological role of Taurine in mammalian tissues, Taurine Transporter-(TauT-) knockout models were recently generated. TauTKO mice exhibited loss of body weight, abnormal cardiac function and the reduced exercise capacity with tissue Taurine depletion. In this chapter, we summarize pathological profile and histological feature of heart and skeletal muscle in TauTKO mice.
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Involvement of Transcriptional Factor TonEBP in the Regulation of the Taurine Transporter in the Cardiomyocyte
Advances in experimental medicine and biology, 2009Co-Authors: Takashi Ito, Stephen W. Schaffer, Yasushi Fujio, Junichi AzumaAbstract:Taurine is found in high concentrations in heart where it exerts several actions that could potentially benefit the diseased heart. The Taurine Transporter (TauT) is crucial for the maintenance of high Taurine levels in the heart. Although cardiac Taurine content is altered in various pathological conditions, little is known about the regulatory mechanisms governing TauT expression in cardiac myocytes. In the present study, we found that treatment with the antineoplastic drug doxorubicin (DOX), which is also known as a cardiotoxic agent, decreases the expression of the TauT gene in cultured cardiomyocytes isolated from the neonatal rat heart. Based on data obtained using a luciferase assay, DOX significantly reduced transcriptional activity driven by the TauT promoter, while deletion or mutation of a tonicity-response element (TonE) in this promoter eliminated the change of promoter activity. The protein level of the TonE-binding protein (TonEBP) was reduced by DOX treatment. In addition, the reduction in TonEBP protein content was suppressed by proteasome inhibitors. In conclusion, the DOX-enhanced degradation of TonEBP resulting in reduced TauT expression in the cardiomyocyte.
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Taurine Transporter in primary cultured neonatal rat heart cells: a comparison between cardiac myocytes and nonmyocytes.
Biochemical pharmacology, 2003Co-Authors: Kyoko Takahashi, Koichi Takahashi, Stephen W. Schaffer, Mistuhiro Azuma, Tomoko Yamada, Yuko Ohyabu, Junichi AzumaAbstract:Abstract In the present study, we examined the characteristics of the Taurine Transporter and the intracellular Taurine content in cultured neonatal heart cells. Primary cultures of cardiac myocytes and cardiac fibroblasts (nonmyocytes) were prepared from 1-day-old Wistar rats. The parameters examined were: (a) intracellular Taurine content by the HPLC method, (b) the expression levels of Taurine Transporter mRNA and protein using northern and western blot analysis, and (c) Transporter activity determined by the uptake of 3 H -labeled Taurine. The Taurine content of myocytes was significantly higher (3-fold) than that of nonmyocytes. Taurine Transporter mRNA was strongly expressed in both myocytes and nonmyocytes, whereas the magnitude [normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene expression] of the Transporter mRNA expressed in myocytes was lower than that in nonmyocytes. The expression level of Transporter protein in myocytes was also lower than that of nonmyocytes. Uptake of radiolabeled Taurine into monolayer cultures of heart cells was stimulated markedly by the presence of Na + in the medium, whereas this uptake was almost abolished in the absence of Na + . The Na + /Taurine stoichiometry was 2:1 for both myocytes and nonmyocytes. Kinetic analysis showed that a single saturable system was involved in Taurine uptake into both cell types. In myocytes, the apparent K m and V max values for the Transporter were 20.7±0.5 μM and 1.07±0.01 nmol/10 6 cells/30 min, respectively. Similarly, those of nonmyocytes were 20.3±0.7 μM and 0.42±0.01 nmol/10 6 cells/30 min. These findings indicated that both myocytes and nonmyocytes expressed an identical Taurine Transporter with a Michaelis–Menten constant of 20–21 μM and that a higher Taurine content in myocytes may be associated with a higher V max .
