Russ Lebovitz - Academia.edu (original) (raw)

Papers by Russ Lebovitz

Alzheimer's & dementia, May 21, 2024

European journal of neurology, Jan 25, 2024

Parkinsonism & Related Disorders, Aug 1, 2023

Laboratory investigation; a journal of technical methods and pathology, 1996

We targeted a mutant p53 gene (val135), previously shown to cause tumors in transgenic mice, to t... more We targeted a mutant p53 gene (val135), previously shown to cause tumors in transgenic mice, to the kidney and eye using a gamma-glutamyltranspeptidase promoter. Although transgene RNA was expressed in both tissues, and mutant protein could be detected at high levels in the kidney and was appropriately localized to the nuclei of proximal tubules, no gross or microscopic lesions developed, even when mice were held as long as 75 weeks. When these mice were crossed with transgenic mice carrying HrasT24 (containing a codon 12 mutation) driven by the same promoter, the p53val135 transgene partially suppressed the mutant ras phenotype (proximal tubular hyperplasia and adenomas and carcinomas of the ciliary body and retinal pigment epithelium). The kidneys of double transgenic mice younger than 25 weeks showed less tubular hyperplasia and cystic change than littermates carrying gamma-glutamyltranspeptidase(I)rasT24 alone. By 33 weeks, there was no difference in the severity of the kidney l...

Laboratory investigation; a journal of technical methods and pathology, 1995

Although prostate cancer is one of the most prevalent tumors in men, knowledge of its biology has... more Although prostate cancer is one of the most prevalent tumors in men, knowledge of its biology has been hindered by lack of animal models. We have attempted to develop a prostate cancer model utilizing transgenic mouse technology. Two lines of transgenic mice were derived from one cell stage embryos injected with a fusion gene consisting of a mutated (codon 12) ras gene driven by the human prostate specific antigen (PSA) promoter in an attempt to target the oncogene specifically to the mouse prostate gland. Nontransgenic FVB/N mice were used as controls. The animals were sacrificed for study between 4 and 55 weeks of age. All organs were normal except the salivary glands and gastrointestinal tracts, both of which developed carcinomas in animals older than 44 weeks. The salivary gland tumors were of ductal origin, exhibited a variable degree of differentiation, and were shown to contain abundant PSAras mRNA by in situ hybridization. The gastrointestinal tract tumors were undifferentia...

The American journal of pathology, 1993

We examined eye lesions in five lines of transgenic mice carrying the human rasT24 oncogene drive... more We examined eye lesions in five lines of transgenic mice carrying the human rasT24 oncogene driven by the type I gamma glutamyl transferase (gamma GT) promoter. In three lines, hyperplasia developed as early as 11.5 days postconception in the outer neuroectodermal layer, which gives rise to ciliary body and retinal pigment epithelium. At birth, the eyes from many animals contained adenomas, and by day 27, mice developed invasive adenocarcinomas originating in the region of the ciliary body. Microphthalmia, cataracts, and chronic nongranulomatous inflammation involving the anterior and/or posterior segments of the eye were also found. gamma GT is detectable histochemically as early as 11.5 gestational days in the outer neuroectodermal layer and after birth is more abundant in the ciliary body than in the retinal pigment epithelium. Using a reverse transcriptase-polymerase chain reaction, we found that type I (but not types II or III) gamma GT RNA is made by the mouse eye; the gamma G...

The American journal of pathology, 1993

Five families of transgenic mice were derived from one-cell-stage embryos injected with gamma GT-... more Five families of transgenic mice were derived from one-cell-stage embryos injected with gamma GT-rasT24, a fusion gene consisting of the gamma-glutamyl transpeptidase (gamma GT) 5' flanking region containing promoter I linked to a mutated (codon 12) human H-ras oncogene. The transgene was expressed selectively in the kidneys, eyes, and brains of all families as determined by reverse transcription-polymerase chain reaction, nuclease protection assays, and in situ hybridization. In two of five families, kidney lesions consisting of proximal tubular hyperplasia, renal cysts, and microadenomas developed in male animals; males also expressed higher levels of gamma GT/rasT24 RNA. Early lesions consisted of proximal tubular hyperplasia as defined by alkaline phosphatase histochemistry, gamma GT immunohistochemistry, and electron microscopy and could be correlated with the presence of rasT24 RNA within the cystic proximal tubular epithelium by in situ hybridization. Advanced lesions als...

Proceedings of the National Academy of Sciences, 1996

gamma-Glutamyl transpeptidase (GGT) is an ectoenzyme that catalyzes the first step in the cleavag... more gamma-Glutamyl transpeptidase (GGT) is an ectoenzyme that catalyzes the first step in the cleavage of glutathione (GSH) and plays an essential role in the metabolism of GSH and GSH conjugates of carcinogens, toxins, and eicosanoids. To learn more about the role of GGT in metabolism in vivo, we used embryonic stem cell technology to generate GGT-deficient (GGTm1/GGTm1) mice. GGT-deficient mice appear normal at birth but grow slowly and by 6 weeks are about half the weight of wild-type mice. They are sexually immature, develop cataracts, and have coats with a gray cast. Most die between 10 and 18 weeks. Plasma and urine GSH levels in the GGTm1/GGTm1 mice are elevated 6-fold and 2500-fold, respectively, compared with wild-type mice. Tissue GSH levels are markedly reduced in eye, liver, and pancreas. Plasma cyst(e)ine levels in GGTm1/GGTm1 mice are reduced to approximately 20% of wild-type mice. Oral administration of N-acetylcysteine to GGTm1/GGTm1 mice results in normal growth rates a...

Molecular Endocrinology, 1994

An expression cassette carrying 426 basepairs of the rat probasin (PB) gene promoter and 26 basep... more An expression cassette carrying 426 basepairs of the rat probasin (PB) gene promoter and 26 basepairs of 5'untranslated region is sufficient to target the expression of the bacterial chloramphenicol acetyltransferase (CAT) gene specifically to the prostate in transgenic mice. The PB-CAT transgene was expressed in three of five (60%) independent lines of mice, and this expression, as reported previously for the endogenous rat gene, was male specific, restricted primarily to the lateral, dorsal, and ventral lobes of the prostate, with only very low levels of CAT activity detected in the anterior prostate and seminal vesicles. The developmental and hormonal regulation of the transgene also paralleled that reported for the rat gene, with a 70-fold increase in CAT activity in the mouse prostate observed between 2-7 weeks of age, a time corresponding to sexual maturation. PB-CAT activity in the prostate declined after castration to 3.5% of the precastration level, and the CAT activity in castrated males approached precastration levels when mice were supplemented with testosterone. Transgene expression in castrated males was not induced by dexamethasone. Coinjection of PB-CAT with a chicken lyso-0999~9909/94/0230-0239$03.00/0 Molecular Endocrinology Copyright CD 1994 by The Endocri ne Society zyme gene matrix attachment region resulted in their cointegration and further restricted the pattern of PB-CAT to the dorsolateral prostate, with suppressed expression observed in the ventral prostate. These studies demonstrate that a minimal rat probasin promoter can target heterologous gene expression specifically to the prostate in a developmentally and hormonally regulated fashion.

L'invention concerne une methode permettant d'ameliorer une perte auditive, une lesion in... more L'invention concerne une methode permettant d'ameliorer une perte auditive, une lesion indirecte de la chimiotherapie ou une mucosite chez un animal. Cette methode consiste a administrer une composition comprenant un fullerene substitue a un mammifere souffrant d'une perte auditive, d'une lesion indirecte de chimiotherapie ou de mucosite, ou predispose a une perte auditive, a une lesion indirecte de chimiotherapie ou a une mucosite. Le fullerene substitue comprend un noyau de fullerene (Cn) et au moins un element parmi: (i) de 1 a 3 groupes (>CX1X2) relies au noyau de fullerene; (ii) de 1 a 18 groupes X3 relies au noyau de fullerene; (iii) de 1 a 6 groupes X4 relies au noyau de fullerene; ou (iv) de 1 a 6 dendrites reliees au noyau de fullerene.

La presente invention decrit l'emploi de fullerenes substitues dans le traitement d'etats... more La presente invention decrit l'emploi de fullerenes substitues dans le traitement d'etats de choc. Lesdits fullerenes substitues comprennent un noyau fullerene (Cn) et au moins un membre du groupe constitue par : (i) entre (1) et (6) groupements (>CX1X2) lies au noyau fullerene ; (ii) entre (1) et (18) groupements -X3 lies au noyau fullerene ; (iii) entre (1) et (6) groupements -X4- lies au noyau fullerene ; ou (iv) entre (1) et (6) dendrites liees au noyau fullerene.

American Journal Of Pathology

gamma-Glutamyl transpeptidase is a key enzyme in glutathione (GSH) salvage, metabolism of endogen... more gamma-Glutamyl transpeptidase is a key enzyme in glutathione (GSH) salvage, metabolism of endogenous mediators such as leukotrienes and prostaglandins, detoxification of xenobiotics including environmentally important compounds and carcinogens, and cellular processes dependent on the oxidation/reduction of glutathione. The enzyme is widely distributed, and these functions often occur in separate tissues and in response to different stimuli. Evidence indicates that gamma-glutamyl transpeptidase plays a direct role in some hepatic and renal responses to injury. In the mouse gamma-glutamyl transpeptidase is a single copy gene expressed from at least seven promoters, and many of the transcribed gamma-glutamyl transpeptidase RNAs are restricted in their expression. Studies that combine analyses of cellular processes with a knowledge of gene structure and expression hold promise for unravelling how these two different levels of function are integrated.

Journal of Biological Chemistry

Mouse gamma-glutamyl transpeptidase (gamma GT) is encoded by a single copy gene with at least fiv... more Mouse gamma-glutamyl transpeptidase (gamma GT) is encoded by a single copy gene with at least five and probably six different promoters directing the transcription of six types of gamma GT RNAs. In mouse small intestine, only Type I, V, and VI gamma GT RNAs are detected, and ribonuclease protection assays reveal that Type VI represents more than 90% of gamma GT RNA. To investigate the structure of intestinal gamma GT RNA in greater detail, we cloned and sequenced mouse intestinal gamma GT cDNAs. Seven of eight informative clones were Type VI and consisted of Type VI unique exons, VIa and VIb (as described previously by us) (Rajagopalan, S., Wan, D.-F., Habib, G. M., Sepulveda, A. R., McLeod, M. R., Lebovitz, R. M., and Lieberman, M. W. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 6179-6183) as well as common 3' sequences. Exon VIb contains two alternative splice acceptors, one previously identified by us and the other 17 bases 5' of this site. Another clone contained a previousl...

Alzheimer's & dementia, May 21, 2024

European journal of neurology, Jan 25, 2024

Parkinsonism & Related Disorders, Aug 1, 2023

Laboratory investigation; a journal of technical methods and pathology, 1996

We targeted a mutant p53 gene (val135), previously shown to cause tumors in transgenic mice, to t... more We targeted a mutant p53 gene (val135), previously shown to cause tumors in transgenic mice, to the kidney and eye using a gamma-glutamyltranspeptidase promoter. Although transgene RNA was expressed in both tissues, and mutant protein could be detected at high levels in the kidney and was appropriately localized to the nuclei of proximal tubules, no gross or microscopic lesions developed, even when mice were held as long as 75 weeks. When these mice were crossed with transgenic mice carrying HrasT24 (containing a codon 12 mutation) driven by the same promoter, the p53val135 transgene partially suppressed the mutant ras phenotype (proximal tubular hyperplasia and adenomas and carcinomas of the ciliary body and retinal pigment epithelium). The kidneys of double transgenic mice younger than 25 weeks showed less tubular hyperplasia and cystic change than littermates carrying gamma-glutamyltranspeptidase(I)rasT24 alone. By 33 weeks, there was no difference in the severity of the kidney l...

Laboratory investigation; a journal of technical methods and pathology, 1995

Although prostate cancer is one of the most prevalent tumors in men, knowledge of its biology has... more Although prostate cancer is one of the most prevalent tumors in men, knowledge of its biology has been hindered by lack of animal models. We have attempted to develop a prostate cancer model utilizing transgenic mouse technology. Two lines of transgenic mice were derived from one cell stage embryos injected with a fusion gene consisting of a mutated (codon 12) ras gene driven by the human prostate specific antigen (PSA) promoter in an attempt to target the oncogene specifically to the mouse prostate gland. Nontransgenic FVB/N mice were used as controls. The animals were sacrificed for study between 4 and 55 weeks of age. All organs were normal except the salivary glands and gastrointestinal tracts, both of which developed carcinomas in animals older than 44 weeks. The salivary gland tumors were of ductal origin, exhibited a variable degree of differentiation, and were shown to contain abundant PSAras mRNA by in situ hybridization. The gastrointestinal tract tumors were undifferentia...

The American journal of pathology, 1993

We examined eye lesions in five lines of transgenic mice carrying the human rasT24 oncogene drive... more We examined eye lesions in five lines of transgenic mice carrying the human rasT24 oncogene driven by the type I gamma glutamyl transferase (gamma GT) promoter. In three lines, hyperplasia developed as early as 11.5 days postconception in the outer neuroectodermal layer, which gives rise to ciliary body and retinal pigment epithelium. At birth, the eyes from many animals contained adenomas, and by day 27, mice developed invasive adenocarcinomas originating in the region of the ciliary body. Microphthalmia, cataracts, and chronic nongranulomatous inflammation involving the anterior and/or posterior segments of the eye were also found. gamma GT is detectable histochemically as early as 11.5 gestational days in the outer neuroectodermal layer and after birth is more abundant in the ciliary body than in the retinal pigment epithelium. Using a reverse transcriptase-polymerase chain reaction, we found that type I (but not types II or III) gamma GT RNA is made by the mouse eye; the gamma G...

The American journal of pathology, 1993

Five families of transgenic mice were derived from one-cell-stage embryos injected with gamma GT-... more Five families of transgenic mice were derived from one-cell-stage embryos injected with gamma GT-rasT24, a fusion gene consisting of the gamma-glutamyl transpeptidase (gamma GT) 5' flanking region containing promoter I linked to a mutated (codon 12) human H-ras oncogene. The transgene was expressed selectively in the kidneys, eyes, and brains of all families as determined by reverse transcription-polymerase chain reaction, nuclease protection assays, and in situ hybridization. In two of five families, kidney lesions consisting of proximal tubular hyperplasia, renal cysts, and microadenomas developed in male animals; males also expressed higher levels of gamma GT/rasT24 RNA. Early lesions consisted of proximal tubular hyperplasia as defined by alkaline phosphatase histochemistry, gamma GT immunohistochemistry, and electron microscopy and could be correlated with the presence of rasT24 RNA within the cystic proximal tubular epithelium by in situ hybridization. Advanced lesions als...

Proceedings of the National Academy of Sciences, 1996

gamma-Glutamyl transpeptidase (GGT) is an ectoenzyme that catalyzes the first step in the cleavag... more gamma-Glutamyl transpeptidase (GGT) is an ectoenzyme that catalyzes the first step in the cleavage of glutathione (GSH) and plays an essential role in the metabolism of GSH and GSH conjugates of carcinogens, toxins, and eicosanoids. To learn more about the role of GGT in metabolism in vivo, we used embryonic stem cell technology to generate GGT-deficient (GGTm1/GGTm1) mice. GGT-deficient mice appear normal at birth but grow slowly and by 6 weeks are about half the weight of wild-type mice. They are sexually immature, develop cataracts, and have coats with a gray cast. Most die between 10 and 18 weeks. Plasma and urine GSH levels in the GGTm1/GGTm1 mice are elevated 6-fold and 2500-fold, respectively, compared with wild-type mice. Tissue GSH levels are markedly reduced in eye, liver, and pancreas. Plasma cyst(e)ine levels in GGTm1/GGTm1 mice are reduced to approximately 20% of wild-type mice. Oral administration of N-acetylcysteine to GGTm1/GGTm1 mice results in normal growth rates a...

Molecular Endocrinology, 1994

An expression cassette carrying 426 basepairs of the rat probasin (PB) gene promoter and 26 basep... more An expression cassette carrying 426 basepairs of the rat probasin (PB) gene promoter and 26 basepairs of 5'untranslated region is sufficient to target the expression of the bacterial chloramphenicol acetyltransferase (CAT) gene specifically to the prostate in transgenic mice. The PB-CAT transgene was expressed in three of five (60%) independent lines of mice, and this expression, as reported previously for the endogenous rat gene, was male specific, restricted primarily to the lateral, dorsal, and ventral lobes of the prostate, with only very low levels of CAT activity detected in the anterior prostate and seminal vesicles. The developmental and hormonal regulation of the transgene also paralleled that reported for the rat gene, with a 70-fold increase in CAT activity in the mouse prostate observed between 2-7 weeks of age, a time corresponding to sexual maturation. PB-CAT activity in the prostate declined after castration to 3.5% of the precastration level, and the CAT activity in castrated males approached precastration levels when mice were supplemented with testosterone. Transgene expression in castrated males was not induced by dexamethasone. Coinjection of PB-CAT with a chicken lyso-0999~9909/94/0230-0239$03.00/0 Molecular Endocrinology Copyright CD 1994 by The Endocri ne Society zyme gene matrix attachment region resulted in their cointegration and further restricted the pattern of PB-CAT to the dorsolateral prostate, with suppressed expression observed in the ventral prostate. These studies demonstrate that a minimal rat probasin promoter can target heterologous gene expression specifically to the prostate in a developmentally and hormonally regulated fashion.

L'invention concerne une methode permettant d'ameliorer une perte auditive, une lesion in... more L'invention concerne une methode permettant d'ameliorer une perte auditive, une lesion indirecte de la chimiotherapie ou une mucosite chez un animal. Cette methode consiste a administrer une composition comprenant un fullerene substitue a un mammifere souffrant d'une perte auditive, d'une lesion indirecte de chimiotherapie ou de mucosite, ou predispose a une perte auditive, a une lesion indirecte de chimiotherapie ou a une mucosite. Le fullerene substitue comprend un noyau de fullerene (Cn) et au moins un element parmi: (i) de 1 a 3 groupes (>CX1X2) relies au noyau de fullerene; (ii) de 1 a 18 groupes X3 relies au noyau de fullerene; (iii) de 1 a 6 groupes X4 relies au noyau de fullerene; ou (iv) de 1 a 6 dendrites reliees au noyau de fullerene.

La presente invention decrit l'emploi de fullerenes substitues dans le traitement d'etats... more La presente invention decrit l'emploi de fullerenes substitues dans le traitement d'etats de choc. Lesdits fullerenes substitues comprennent un noyau fullerene (Cn) et au moins un membre du groupe constitue par : (i) entre (1) et (6) groupements (>CX1X2) lies au noyau fullerene ; (ii) entre (1) et (18) groupements -X3 lies au noyau fullerene ; (iii) entre (1) et (6) groupements -X4- lies au noyau fullerene ; ou (iv) entre (1) et (6) dendrites liees au noyau fullerene.

American Journal Of Pathology

gamma-Glutamyl transpeptidase is a key enzyme in glutathione (GSH) salvage, metabolism of endogen... more gamma-Glutamyl transpeptidase is a key enzyme in glutathione (GSH) salvage, metabolism of endogenous mediators such as leukotrienes and prostaglandins, detoxification of xenobiotics including environmentally important compounds and carcinogens, and cellular processes dependent on the oxidation/reduction of glutathione. The enzyme is widely distributed, and these functions often occur in separate tissues and in response to different stimuli. Evidence indicates that gamma-glutamyl transpeptidase plays a direct role in some hepatic and renal responses to injury. In the mouse gamma-glutamyl transpeptidase is a single copy gene expressed from at least seven promoters, and many of the transcribed gamma-glutamyl transpeptidase RNAs are restricted in their expression. Studies that combine analyses of cellular processes with a knowledge of gene structure and expression hold promise for unravelling how these two different levels of function are integrated.

Journal of Biological Chemistry

Mouse gamma-glutamyl transpeptidase (gamma GT) is encoded by a single copy gene with at least fiv... more Mouse gamma-glutamyl transpeptidase (gamma GT) is encoded by a single copy gene with at least five and probably six different promoters directing the transcription of six types of gamma GT RNAs. In mouse small intestine, only Type I, V, and VI gamma GT RNAs are detected, and ribonuclease protection assays reveal that Type VI represents more than 90% of gamma GT RNA. To investigate the structure of intestinal gamma GT RNA in greater detail, we cloned and sequenced mouse intestinal gamma GT cDNAs. Seven of eight informative clones were Type VI and consisted of Type VI unique exons, VIa and VIb (as described previously by us) (Rajagopalan, S., Wan, D.-F., Habib, G. M., Sepulveda, A. R., McLeod, M. R., Lebovitz, R. M., and Lieberman, M. W. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 6179-6183) as well as common 3' sequences. Exon VIb contains two alternative splice acceptors, one previously identified by us and the other 17 bases 5' of this site. Another clone contained a previousl...