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Biomedical subjects

D H Dreyfus

Publications and source records attributed to D H Dreyfus.

12 recordsLinked to original sources
PubMed2000

Stable expression of Epstein-Barr virus BZLF-1-encoded ZEBRA protein activates p53-dependent transcription in human Jurkat T-lymphoblastoid cells.

Interaction between viral proteins and tumor suppressor p53 is a common mechanism of viral pathogenesis. The Epstein-Barr virus (EBV) BZLF-1 ORF-encoded ZEBRA protein (also denoted EB1, Z, Zta) binds to p53 in vitro and has been associated with the altered transcription of p53-regulated genes in B lymphocytes and epithelial cells. In this work, Jurkat T-lymphoblastoid cells that express ZEBRA were characterized by the use of transiently transfected p53 and p53 reporter genes. Stable expression of ZEBRA was associated with the activation of p53-dependent transcription and increased p53 dependent apoptotic cell death. In Jurkat cell lines, stably expressed ZEBRA protein was apparently localized to the cell cytoplasm, in contrast to the typical nuclear localization of this protein in other cell types. Previous studies have suggested that EBV infection of T lymphocytes may contribute to the malignant transformation of T cells and the increased replication of human immunodeficiency virus. Our observations suggest a mechanism through which ZEBRA protein expressed in human T lymphocytes could alter T-cell proliferation and apoptosis during EBV infection. (Blood. 2000;96:625-634)

Apoptosis↗
PubMed1999

Inactivation of NF-kappaB by EBV BZLF-1-encoded ZEBRA protein in human T cells.

We have previously shown that the EBV ZEBRA protein (also denoted EB1, Z, or Zta) encoded by the BZLF open reading frame is expressed in primary human thymocytes and in human T lymphoblastoid cell lines infected by EBV. Expression of EBV-encoded gene products in T lymphocytes could contribute to viral pathogenesis during acute EBV infection as well as in individuals coinfected with EBV and HIV. HPB-ALL and Jurkat T lymphoblastoid cell lines transiently and stably expressing ZEBRA were characterized in this work. Expression of ZEBRA protein in human T lymphoblastoid cells was associated with decreased expression of an NF-kappaB reporter gene, altered expression of the NF-kappaB p50 protein subunit, and decreased DNA binding by components of NF-kappaB. These observations suggest that inactivation of NF-kappaB transcription by ZEBRA in EBV-infected T cells may be a novel mechanism of viral pathogenesis analogous in part to over-expression of the endogenous cytoplasmic inhibitor of NF-kappaB, IkappaBalpha.

DNA-Binding Proteins↗
PubMed1999

Comparative analysis of invertebrate Tc6 sequences that resemble the vertebrate V(D)J recombination signal sequences (RSS).

Invertebrate cells lack the p53 recombination checkpoint but contain mobile DNA sequences that transpose by a mechanism in part shared with excision of the V(D)J recombination signal sequences (RSS). In this work, inversion, deletion, and duplication of sequences associated with an invertebrate C. elegans Tc6 element is described. The structure of this C. elegans sequence and other dispersed Tc6 elements suggests that covalently closed 'hairpin' structures are not unique to excision of the V(D)J RSS by the RAG proteins, but rather can be generated by transposases at transposon termini leading to characteristic inversion and duplication events. Comparative analysis of recombination events at invertebrate sequences resembling the vertebrate V(D)J RSS may be useful in understanding V(D)J recombination-mediated recombination events in malignant vertebrate cells or genetic diseases such as ataxia telangectasia, in which the p53 recombination checkpoint is defective.

Animals↗
PubMed1999

Asymmetric DDE (D35E)-like sequences in the RAG proteins: implications for V(D)J recombination and retroviral pathogenesis.

Experimental evidence suggests that the mechanism of vertebrate V(D)J recombination catalyzed by the vertebrate RAG proteins is similar to both retroviral integration and the transposition of IS630/Tc1-family transposons. The mechanism of both retroviral integration and IS630/Tc1 element transposition is well characterized and utilizes a functional metal ion binding site termed the DDE (or D35E) motif. We have previously identified a DDE-like region in the RAG-2 protein and a similar region within the RAG-1 protein. In this work, we propose that interference between DDE-like regions in the RAG proteins and the DDE-site of the HIV integrase may be a mechanism of retroviral pathogenesis in cells in which both the RAG proteins and retroviral integrase are co-expressed.

Amino Acid Sequence↗
PubMed1996

EBV infection of T cells: potential role in malignant transformation.

The presence of Epstein-Barr virus in different T-cell malignancies is now widely reported. In an effort to ascertain whether T cells are susceptible to EBV infection, we and others have detected the EBV receptor, CD21 on a population of immature thymocytes. We showed that EBV is a cofactor in stimulating proliferation of thymocytes. This proliferation may be a relevant factor in EBV-associated T-cell malignancies as well as EBV causation of acute infectious mononucleosis (AIM). We have further identified a subset of thymocytes that is infectable by EBV in which the genome remains linear in the first weeks after infection. We documented the transcription of the switch protein ZEBRA, an alternatively spliced form, RAZ, and EBNA-1 transcription from the Fp promoter. We hypothesise that EBV may be a cofactor in oncogenesis in T cells through several different pathways.

B-Lymphocytes↗
PubMed1996

Steroid-resistant chronic urticaria associated with anti-thyroid microsomal antibodies in a nine-year-old boy.

The case of a 9-year-old boy with severe chronic urticaria of 6 months' duration is described. The urticaria was associated with intractable bronchospasm and abdominal cramping and was unresponsive to antihistamines and high doses of corticosteroids. Even though the child was euthyroid, he was treated with thyroid hormone after the presence of anti-thyroid microsomal antibodies was documented. Within 1 month the patient demonstrated full remission. He remained free of symptoms for 9 months after discontinuation of treatment. After a relapse he again responded to thyroid hormone therapy. Children with chronic, intractable urticaria and documented evidence of anti-thyroid microsomal antibodies may benefit from treatment with thyroid hormone.

Adrenal Cortex Hormones↗
PubMed1996

Cystic fibrosis 3849+10kb C > T mutation associated with severe pulmonary disease and male fertility.

A 40-yr-old Hispanic man presented to NJCIRM with end-stage lung disease. Evaluation of this patient 10 yr earlier noted bronchiectasis, normal sweat electrolytes, pancreatic sufficiency, delayed progression of pulmonary disease, and a sperm biopsy consistent with fertility. At the time of admission bronchiectasis was extensive. DNA testing demonstrated homozygosity for the 3849+10kb C > T cystic fibrosis (CF) allele. This is the first description of homozygous expression of this allele in a male patient. Confirmation of fertility was established by demonstrating that his children were carriers of this allele. This patient emphasizes the importance of DNA testing for atypical CF alleles in patients with bronchiectasis of undetermined cause even in the presence of fertility, normal pancreatic function, and normal sweat electrolytes.

Adult↗
PubMed1995

Epstein-Barr virus replicative gene transcription during de novo infection of human thymocytes: simultaneous early expression of BZLF-1 and its repressor RAZ.

Epstein-Barr virus (EBV) is known to infect B cells and epithelial cells. We and others have shown that EBV can also infect a subset of thymocytes. Infection of thymocytes was accompanied by the appearance of linear EBV genome within 8 hr of infection. Circularization of the EBV genome was not detected. This is in contrast to the infection in B cells where the genome can circularize within 24 hr of infection. The appearance of the BamHI ZLF-1 gene product, ZEBRA, by RT-PCR, was observed within 8 hr of infection. The appearance of a novel fusion transcript (RAZ), which comprised regions of the BZLF-1 locus and the adjacent BRLF-1 locus, was detected by RT-PCR. ZEBRA protein was also identified in infected thymocytes by immunoprecipitation. In addition, we demonstrated that the EBNA-1 gene in infected thymocytes was transcribed from the Fp promoter, rather than from the Cp/Wp promoter which is used in latently infected B cells. Transcripts encoding gp350/220, the major coat protein of EBV, were identified, but we did not find any evidence of transcription from the LMP-2A or EBER-1 loci in infected thymocytes. These observations suggest that de novo EBV infection of thymocytes differs from infection of B cells. The main difference is that with thymocytes, no evidence could be found that the virus ever circularizes. Rather, EBV remains in a linear configuration from which replicative genes are transcribed.

Antigens, Viral↗
PubMed1995

Four new adenosine deaminase mutations, altering a zinc-binding histidine, two conserved alanines, and a 5' splice site.

Three new missense mutations (H15D, A83D, and A179D) and a new splicing defect (573 + IG-->A) in the 5' splice site of intron 5 were among six mutant adenosine deaminase (ADA) alleles found in three unrelated patients with severe combined immunodeficiency disease, the most common phenotype associated with ADA deficiency. When expressed in vitro, the H15D, A83D, and A179D proteins lacked detectable ADA activity. The splicing defect caused skipping of exon 5, resulting in premature termination of translation and a reduced level of mRNA. H15D is the first naturally occurring mutation of a residue that coordinates directly with the enzyme-associated zinc ion. Molecular modeling based on the atomic coordinates of murine ADA suggests that the D15 mutation would create a cavity or gap between the zinc ion and the side chain carboxylate of D15. This could alter the ability of zinc to activate a water molecule postulated to play a role in the catalytic mechanism. A83 and A179 are not directly involved in the active site, but are conserved residues located respectively in alpha helix 4 and beta strand 4 of the alpha/beta barrel. Replacement of these small hydrophobic Ala residues with the charged, more bulky Asp side chain may distort ADA structure and affect enzyme stability or folding.

Adenosine Deaminase↗
PubMed1991

A transposon-related palindromic repetitive sequence from C. elegans.

A family of transposon-like sequences in the C. elegans genome is described. This family, termed the Tc6 family, consists mostly of conserved, 1.6 kb elements. Four Tc6 elements or partial elements have been cloned and the DNA sequences of three were determined. One appears to be a complete element of 1603 nucleotides, consisting of a palindrome of 765 nucleotides, with a central, non-palindromic region of 73 nucleotides. Another has an identical structure except for an internal deletion. A third is a partial element terminating at a probable internal restriction site used for cloning. A fourth clone contained portions of the Tc6 sequence juxtaposed to non-Tc6 sequences. All C. elegans strains examined contain 20-30 Tc6 elements. The ends of Tc6 elements are conserved and have sequence similarity to the ends of C. elegans transposons Tc1 and Tc3. The ends of Tc6 elements also have sequence similarity to the heptamer portion of the immunoglobulin and T-cell receptor recombination signal sequence, raising the possibility of wide phylogenetic conservation of the recombination mechanism. Tc6 elements also share sequence motifs with plant-pathogenic viroid RNA's, possibly indicative of a Tc6 RNA replicative phase.

Animals↗