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L Feigenbaum

Publications and source records attributed to L Feigenbaum.

18 recordsLinked to original sources
PubMed2001

Strength of signaling by CD4 and CD8 coreceptor tails determines the number but not the lineage direction of positively selected thymocytes.

The present study has assessed the impact of the intracellular domains of CD4 and CD8 on positive selection and lineage direction of MHC class I-restricted thymocytes. Contrary to current presumption, we found that the CD4 tail promotes the generation of both CD4+ and CD8+ T cells without preference for the CD4+ T cell lineage. We also found that the identity of the coreceptor tail and hence the strength of coreceptor signaling determine the number of thymocytes undergoing positive selection but not their ultimate CD4/CD8 phenotype. These findings demonstrate that the strength of coreceptor signaling has a significant quantitative but not qualitative impact on positive selection and provide a simple explanation for the greater numbers of CD4+ than CD8+ T cells selected in the normal thymus.

Animals↗
PubMed2001

The CYP2D6 humanized mouse: effect of the human CYP2D6 transgene and HNF4alpha on the disposition of debrisoquine in the mouse.

CYP2D6 is a highly polymorphic human gene responsible for a large variability in the disposition of more than 100 drugs to which humans may be exposed. Animal models are inadequate for preclinical pharmacological evaluation of CYP2D6 substrates because of marked species differences in CYP2D isoforms. To overcome this issue, a transgenic mouse line expressing the human CYP2D6 gene was generated. The complete wild-type CYP2D6 gene, including its regulatory sequence, was microinjected into a fertilized FVB/N mouse egg, and the resultant offspring were genotyped by both polymerase chain reaction and Southern blotting. CYP2D6-specific protein expression was detected in the liver, intestine, and kidney from only the CYP2D6 humanized mice. Pharmacokinetic analysis revealed that debrisoquine (DEB) clearance was markedly higher (94.1 +/- 22.3 l/h/kg), and its half-life significantly reduced (6.9 +/- 1.6 h), in CYP2D6 humanized mice compared with wild-type animals (15.2 +/- 0.9 l/h/kg and 16.5 +/- 4.5 h, respectively). Mutations in hepatic nuclear factor 4alpha (HNF4alpha), a hepatic transcription factor known to regulate in vitro expression of the CYP2D6 gene, could affect the disposition of CYP2D6 drug substrates. To determine whether the HNF4alpha gene modulates in vivo pharmacokinetics of CYP2D6 substrates, a mouse line carrying both the CYP2D6 gene and the HNF4alpha conditional mutation was generated and phenotyped using DEB. After deletion of HNF4alpha, DEB 4-hydroxylase activity in CYP2D6 humanized mice decreased more than 50%. The data presented in this study show that only CYP2D6 humanized mice but not wild-type mice display significant DEB 4-hydroxylase activity and that HNF4alpha regulates CYP2D6 activity in vivo. The CYP2D6 humanized mice represent an attractive model for future preclinical studies on the pharmacology, toxicology, and physiology of CYP2D6-mediated metabolism.

Adrenergic Agents↗
PubMed2001

Selective inhibition of selenocysteine tRNA maturation and selenoprotein synthesis in transgenic mice expressing isopentenyladenosine-deficient selenocysteine tRNA.

Selenocysteine (Sec) tRNA (tRNA([Ser]Sec)) serves as both the site of Sec biosynthesis and the adapter molecule for donation of this amino acid to protein. The consequences on selenoprotein biosynthesis of overexpressing either the wild type or a mutant tRNA([Ser]Sec) lacking the modified base, isopentenyladenosine, in its anticodon loop were examined by introducing multiple copies of the corresponding tRNA([Ser]Sec) genes into the mouse genome. Overexpression of wild-type tRNA([Ser]Sec) did not affect selenoprotein synthesis. In contrast, the levels of numerous selenoproteins decreased in mice expressing isopentenyladenosine-deficient (i(6)A(-)) tRNA([Ser]Sec) in a protein- and tissue-specific manner. Cytosolic glutathione peroxidase and mitochondrial thioredoxin reductase 3 were the most and least affected selenoproteins, while selenoprotein expression was most and least affected in the liver and testes, respectively. The defect in selenoprotein expression occurred at translation, since selenoprotein mRNA levels were largely unaffected. Analysis of the tRNA([Ser]Sec) population showed that expression of i(6)A(-) tRNA([Ser]Sec) altered the distribution of the two major isoforms, whereby the maturation of tRNA([Ser]Sec) by methylation of the nucleoside in the wobble position was repressed. The data suggest that the levels of i(6)A(-) tRNA([Ser]Sec) and wild-type tRNA([Ser]Sec) are regulated independently and that the amount of wild-type tRNA([Ser]Sec) is determined, at least in part, by a feedback mechanism governed by the level of the tRNA([Ser]Sec) population. This study marks the first example of transgenic mice engineered to contain functional tRNA transgenes and suggests that i(6)A(-) tRNA([Ser]Sec) transgenic mice will be useful in assessing the biological roles of selenoproteins.

Animals↗
PubMed2001

Suppression of T-cell responsiveness by inducible cAMP early repressor (ICER).

Depending on the nature of the costimulation of T lymphocytes, expression of regulatory cytokines and chemokines is either susceptible or resistant to cyclic AMP (cAMP)-mediated inhibition. Our data show that cAMP-mediated inhibition of endogenously expressed cytokines, which is characteristic for T helper (Th) 1- and Th 2-like phenotypes, correlates with the induction of a potent transcriptional repressor, inducible cAMP early repressor (ICER), in both subsets of T cells activated under conditions of suboptimal interleukin-2 (IL-2) expression. Importantly, Th-specific expression of certain chemokines is also susceptible to cAMP-mediated transcriptional attenuation. To determine whether ICER per se, rather than forskolin-mediated elevation of intracellular cAMP, is responsible for the observed inhibitory effect, we generated transgenic mice expressing ICER under the control of a lymphocyte-specific lck promoter. On stimulation, transgenic thymocytes overexpressing ICER exhibited reduced levels of IL-2 and interferon (IFN)-gamma and failed to express the macrophage inflammatory protein (MIP)-1alpha and MIP-1beta genes. Splenic T cells from ICER-transgenic mice showed a defect in proliferation and lacked a mixed lymphocyte reaction response, implying that ICER-mediated inhibition of cytokine and chemokine expression might play an important role in T-cell inactivation.

Animals↗
PubMed2000

Burkitt lymphoma in the mouse.

Chromosomal translocations juxtaposing the MYC protooncogene with regulatory sequences of immunoglobulin (Ig) H chain or kappa (Ig kappa) or lambda (Ig lambda) L chain genes and effecting deregulated expression of MYC are the hallmarks of human Burkitt lymphoma (BL). Here we report that lymphomas with striking similarities to BL develop in mice bearing a mutated human MYC gene controlled by a reconstructed Ig lambda locus encompassing all the elements required for establishment of locus control in vitro. Diffusely infiltrating lymphomas with a typical starry sky appearance occurred in multiple founders and an established line, indicating independence from positional effects. Monoclonal IgM(+)CD5(-)CD23(-) tumors developed from an initially polyclonal population of B cells. These results demonstrate that the phenotype of B lineage lymphomas induced by MYC dysregulation is highly dependent on cooperativity among the regulatory elements that govern expression of the protooncogene and provide a new system for studying the pathogenesis of BL.

Animals↗
PubMed2000

IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice.

A transgenic (Tg) mouse expressing human IL-15 was generated to define the role of IL-15 in the normal immune response. Overexpression of IL-15 resulted in an increase of NK, CD44(hi)CD8 memory T cells, and gammadelta T cells. Additionally, we observed the emergence of a novel type of NK-T cells with CD8alphaalpha' expression. Due to the expansion and activation of NK cells, the IL-15Tg mouse showed enhanced innate immunity. In adaptive T cell immunity, the roles of IL-15 contrasted with those of IL-2. IL-15 inhibited IL-2-induced T cell death, which plays a role in the maintenance of peripheral self-tolerance. IL-15 thus seems to contribute to enhanced immune memory by selectively propagating memory T cells and by blocking T cell death mediated by IL-2.

Animals↗
PubMed2000

Role of CD8beta domains in CD8 coreceptor function: importance for MHC I binding, signaling, and positive selection of CD8+ T cells in the thymus.

The contribution of the CD8beta subunit to CD8 coreceptor function is poorly understood. We now demonstrate that the CD8beta extracellular domain increases the avidity of CD8 binding to MHC I, and that the intracellular domain of CD8beta enhances association with two intracellular molecules required for TCR signal transduction, Lck and LAT. By assessing CD8+ T cell differentiation in CD8beta-deficient mice reconstituted with various transgenic CD8beta chimeric molecules, we also demonstrate that the intracellular and extracellular domains of CD8beta can contribute independently to CD8+ T cell development, but that both CD8beta domains together are most efficient. Thus, this study identifies the molecular functions of the CD8beta intracellular and extracellular domains and documents their contributions to CD8+ T cell development.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Life without white fat: a transgenic mouse.

We have generated a transgenic mouse with no white fat tissue throughout life. These mice express a dominant-negative protein, termed A-ZIP/F, under the control of the adipose-specific aP2 enhancer/promoter. This protein prevents the DNA binding of B-ZIP transcription factors of both the C/EBP and Jun families. The transgenic mice (named A-ZIP/F-1) have no white adipose tissue and dramatically reduced amounts of brown adipose tissue, which is inactive. They are initially growth delayed, but by week 12, surpass their littermates in weight. The mice eat, drink, and urinate copiously, have decreased fecundity, premature death, and frequently die after anesthesia. The physiological consequences of having no white fat tissue are profound. The liver is engorged with lipid, and the internal organs are enlarged. The mice are diabetic, with reduced leptin (20-fold) and elevated serum glucose (3-fold), insulin (50- to 400-fold), free fatty acids (2-fold), and triglycerides (3- to 5-fold). The A-ZIP/F-1 phenotype suggests a mouse model for the human disease lipoatrophic diabetes (Seip-Berardinelli syndrome), indicating that the lack of fat can cause diabetes. The myriad of consequences of having no fat throughout development can be addressed with this model.

Adipose Tissue↗
PubMed1996

Repression of the NF1 gene by Tax may expain the development of neurofibromas in human T-lymphotropic virus type 1 transgenic mice.

In familial neurofibromatosis type 1 (NF1), individuals with a germ line-transmitted NF1 mutation develop multiple neurofibromas. To explain the observation that transgenic mice expressing the human T-lymphotropic virus type 1 (HTLV-1) tax gene under the control of the viral regulatory element also develop multiple neurofibromas, we demonstrate that the Tax trans-regulator can functionally repress NF1 gene expression through a cis-acting element located immediately upstream of its transcriptional start site, thereby allowing the development of benign neurofibromas without the need for direct mutations in NF1. We propose that such a mechanism would suffice to epigenetically alter NF1 gene expression. The fact that transgenic animals have localized rather than diffuse neurofibroma formation, however, suggests that additional genetic or epigenetic events may be required for neurofibroma formation.

3T3 Cells↗
PubMed1992

JC virus and simian virus 40 enhancers and transforming proteins: role in determining tissue specificity and pathogenicity in transgenic mice.

When introduced into the germ line of mice, the simian virus 40 (SV40) T antigen under the control of its own transcriptional enhancer and promoter selectively induced tumors in the choroid plexus as well as thymic hyperplasia and kidney pathology. In contrast, the JC virus (JCV) T antigen under the control of its own regulatory sequences induced hypomyelination of the central nervous system and tumors of neural origin. Since SV40 and JCV have extensive sequence homology, except for their transcriptional control regions, these observations suggest but do not prove that, although the diseases induced by the two viruses, are consequences of the transforming gene, they are determined predominantly by the respective viral enhancers and promoters. To test this hypothesis, the regulatory regions of the two viruses were exchanged, and transgenic mice were derived with either chimeric construct. Like wild-type JCV, the construct containing the SV40 T antigen under the control of the JCV regulatory region induced hypomyelination of the central nervous system and neural tumors. Surprisingly, mice with this construct also developed choroid plexus carcinomas. Like the wild-type SV40 transgenic mice, mice with the JCV T antigen under the control of the SV40 enhancer and promoter developed choroid plexus tumors and renal pathology. Unexpectedly, they also had hyperplasia of the thyroid follicular cells. These findings not only provide direct evidence for the specificity of the respective viral regulatory region but also, more importantly, show that the transforming genes play a critical role in determining viral pathogenesis.

Animals↗
PubMed1991

Transgenic mouse model for central nervous system demyelination.

A common feature of demyelinating diseases such as multiple sclerosis in humans and experimental autoimmune encephalomyelitis in rodents is the marked elevation in the expression of the major histocompatibility complex (MHC) antigens in the involved sites. By specific targeting of a syngeneic MHC class I gene to oligodendrocytes, we have generated transgenic mice which not only exhibit severe involuntary tremors and develop tonic seizures but also show extensive demyelination in both the brain and the spinal cord. The fact that demyelination in these mice occurs in the absence of immune infiltration dismisses an autoimmune involvement but suggests that the MHC class I antigens play a direct role in inducing disease. Our findings lend support to the possibility that demyelinating diseases are induced by infectious agents such as viruses which can either directly activate MHC gene expression in oligodendroglia or indirectly activate expression through the release by reactive T cells of gamma interferon in the brain.

Animals↗
PubMed1989

Transgenic approach for the study of pathogenesis induced by human viruses.

An understanding of the pathogenesis of human viral diseases has been hampered by the lack of suitable animal models. However, with the advent in the last decade of transgenic technology, it is now possible to introduce one or more viral genes into the germ-line of animals. Thus, transgenic technology allows for the study of viral gene expression and function in the context of the whole animal. The focus of this review is to define the advantages and disadvantages of the transgenic approach in studies of viral pathogenesis. Studies involving a human DNA tumor virus (JCV) and a human retrovirus (HIV) will be described to illustrate these points.

Animals↗
PubMed1987

Evidence for a shift in 5'-termini of early viral RNA during the lytic cycle of JC virus.

We have used primer extension and S1 analysis to localize the 5'-termini of JC virus (JCV) early RNAs in infected primary human fetal glial cells at various times postinfection and in stable JCV-transformed hamster fetal glial cells. At early times postinfection (Days 1-5), two early transcripts are initiated at nucleotides 5122 and 5082. A major shift in 5'-ends at later times results in the synthesis of a new series of early mRNAs beginning upstream at nucleotide 35 and downstream at nucleotides 5047, 5037, and 5012. In the transformed hamster cells, however, only one RNA species was detected, starting at nucleotide 5122. The mechanism underlying the shift in the initiation site of JCV early RNAs during a lytic infection remains unclear but appears analogous to that which occurs in the SV40 lytic cycle. Since the shift occurs during DNA replication, when T-antigen is at maximal levels, it is possible that T-antigen binding to JCV DNA and/or alterations in chromatin structure contribute to this event.

Animals↗
PubMed1987

Regulation of the host range of human papovavirus JCV.

Human papovavirus JCV is associated with the human demyelinating disorder progressive multifocal leukoencephalopathy. In tissue culture, the virus is largely restricted to growth in primary human fetal glial cell. In this study, we demonstrate two levels of regulation of the viral host range. Expression of the early JCV mRNA, which encodes the essential viral protein, large tumor antigen (T antigen), depends on recognition of the early enhancer/promoter elements by tissue-specific factors found in both human and rodent glial cells. In the presence of JCV T antigen, viral DNA replication requires a species-specific factor, presumably a component of DNA polymerase, which is found in a wide range of primate cells. We further demonstrate that simian virus 40 T antigen has sufficient homology to efficiently substitute for the analogous JCV protein in initiating viral DNA replication.

Animals↗
PubMed1986

Trans-activation of the human immunodeficiency virus long terminal repeat sequence by DNA viruses.

To investigate whether DNA viruses can augment gene expression of the human immunodeficiency virus (HIV), cotransfection experiments were carried out in which a recombinant plasmid containing the HIV long terminal repeat (LTR) linked to the chloramphenicol acetyltransferase (CAT) gene was transfected into cultured cells along with plasmids containing DNA from various distinct classes of DNA viruses. Molecular clones containing JC virus, BK virus, lymphotropic papovavirus, bovine papilloma virus, type 1 herpes simplex virus (HSV-1), and varicella-zoster virus sequences increased CAT expression directed by the HIV LTR. Trans-activation of the HIV LTR varied in different cell lines, but in each case the HIV tat gene product elicited the greatest stimulation. Primer-extension assays specific for HIV LTR mRNA revealed increased levels of steady-state RNA following transfection with HIV tat as well as with several of the DNA viruses. Virus-specific RNA expression paralleled the stimulation of CAT activity. More-than-additive effects were observed at both the RNA and protein levels when tat plus type 1 herpes simplex virus DNAs or tat plus JC virus DNAs were transfected into cells with the HIV LTR-CAT plasmid. These data suggest that coinfection of cells by HIV and some DNA viruses can stimulate the expression of HIV.

Antigens, Viral, Tumor↗
PubMed1981

Reduction in oocyte number following prenatal exposure to a diet high in galactose.

When pregnant rats were fed a 50 percent galactose diet there was a striking reduction in oocyte number in the offspring. The most prominent effects were noted after exposure to galactose during the premeiotic stages of oogenesis. Prenatal exposure to galactose or its metabolites may contribute to the premature ovarian failure characteristic of human galactosemia.

Animals↗