Showing papers by "David E. Levy published in 2001"
TL;DR: The long co-evolutionary history of viruses with their hosts has seen the development of a variety of evasive adaptations that allow viruses to circumvent or inactivate host antiviral mechanisms.
425 citations
TL;DR: It is suggested that NS5A inhibits the antiviral actions of IFN by at least two mechanisms and the first evidence for a biological effect of the transcriptional activity of the NS5a protein is provided.
Abstract: Hepatitis C virus (HCV), a major cause of liver disease worldwide, is frequently resistant to the antiviral alpha interferon (IFN). The HCV nonstructural 5A (NS5A) protein has been implicated in HCV antiviral resistance in many studies. NS5A antagonizes the IFN antiviral response in vitro, and one mechanism is via inhibition of a key IFN-induced enzyme, the double-stranded-RNA-activated protein kinase (PKR). In the present study we determined if NS5A uses other strategies to subvert the IFN system. Expression of full-length NS5A proteins from patients who exhibited a complete response (FL-NS5A-CR) or were nonresponsive (FL-NS5A-NR) to IFN therapy in HeLa cells had no effect on IFN induction of IFN-stimulated gene factor 3 (ISGF-3). Expression of mutant NS5A proteins lacking 110 (NS5A-ΔN110), 222 (NS5A-ΔN222), and 334 amino-terminal amino acids and mutants lacking 117 and 230 carboxy-terminal amino acids also had no effect on ISGF-3 induction by IFN. Expression of FL-NS5A-CR and FL-NS5A-NR did not affect IFN-induced STAT-1 tyrosine phosphorylation or upregulation of PKR and major histocompatibility complex class I antigens. However, NS5A expression in human cells induced interleukin 8 (IL-8) mRNA and protein, and this effect correlated with inhibition of the antiviral effects of IFN in an in vitro bioassay. NS5A induced transcription of a reporter gene driven by the IL-8 promoter, and the first 133 bp of the IL-8 promoter made up the minimal domain required for NS5A transactivation. NS5A-ΔN110 and NS5A-ΔN222 stimulated the IL-8 promoter to higher levels than did the full-length NS5A protein, and this correlated with increased nuclear localization of the proteins. Additional mutagenesis of the IL-8 promoter suggested that NF-κB and AP-1 were important in NS5A-ΔN222 transactivation in the presence of tumor necrosis factor alpha and that NF–IL-6 was inhibitory to this process. This study suggests that NS5A inhibits the antiviral actions of IFN by at least two mechanisms and provides the first evidence for a biological effect of the transcriptional activity of the NS5A protein. During HCV infection, viral proteins may induce chemokines that contribute to HCV antiviral resistance and pathogenesis.
335 citations
TL;DR: These findings indicate that Stat3 oncogenic activities could also be mediated through its cooperation with c-Jun, resulting in downregulation of Fas surface expression, which is implicated in the tumor's ability to resist therapy and metastasize.
244 citations
TL;DR: Results suggest that a novel cellular protein that is activated by viral products in addition to dsRNA and is sensitive to E3L inhibition is responsible for IRF activation and reveal a novel mechanism for the anti-IFN effect of E 3L distinct from its inhibition of PKR.
228 citations
TL;DR: The data suggest that STAT C‐termini contribute to the specificity of cellular responses by linking individual STATs to different serine kinase pathways and through an intrinsically different requirement for serine phosphorylation at different target gene promoters.
Abstract: Complete activation of signal transducer and activator of transcription 1 (STAT1) requires phosphorylation at both Y701 and a conserved PMS(727)P sequence. S727 phosphorylation of STAT1 in interferon-gamma (IFN-gamma)-treated mouse fibroblasts occurred without a need for p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1 and 2 or c-Jun kinases, and required both an intact SH2 domain and phosphorylation of Y701. In contrast, UV irradiation-induced STAT1 phosphorylation on S727 required p38MAPK, but no SH2 domain- phosphotyrosine interactions. Mutation of S727 differentially affected IFN-gamma target genes, at the level of both basal and induced expression. Particularly strong effects were noted for the GBP1 and TAP1 genes. The PMS(727)P motif of STAT3 was phosphorylated by stimuli and signaling pathways different from those for STAT1 S727. Transfer of the STAT3 C-terminus to STAT1 changed the stimulus and pathway specificity of STAT1 S727 phosphorylation to that of STAT3. Our data suggest that STAT C-termini contribute to the specificity of cellular responses by linking individual STATs to different serine kinase pathways and through an intrinsically different requirement for serine phosphorylation at different target gene promoters.
203 citations
TL;DR: An essential role for STAT1 is documented in FGF-mediated regulation of cell growth that is specific to the epiphyseal growth plate and that attenuated as the animals grew older.
Abstract: Unregulated FGF receptor signaling results in bone malformations that affect both endochondral and intramembranous ossification, and is the basis for several genetic forms of human dwarfism. FGF signaling inhibits chondrocyte proliferation and we have previously shown that the transcription factor STAT1 mediates the growth inhibitory effect of FGF in vitro. We provide genetic evidence that STAT1 is a modulator of the negative regulation of bone growth by FGF in vivo. We crossed Stat1 −/− mice with a transgenic mouse line overexpressing human FGF2 (TgFGF). TgFGF mice exhibit phenotypes characterized by chondrodysplasia and macrocephaly, which affect endochondral and intramembranous ossification. We found that the chondrodysplasic phenotype of these mice results both from reduced proliferation and increased apoptosis of growth plate chondrocytes. Loss of STAT1 function in TgFGF mice led to a significant correction of the chondrodysplasic phenotype, but did not affect the skull malformations. The reduced proliferation of TgFGF growth plate chondrocytes, as well as their excessive apoptosis, were restored to near-normal levels in the absence of STAT1 function. Unregulated FGF signaling in TgFGF mice also induced apoptosis in calvarial osteoblasts that was not, however, corrected by the absence of STAT1. Detailed analysis of Stat1 −/− growth plates uncovered a transient phenotype, characterized by an expansion of the proliferative zone and by acceleration of longitudinal bone growth, that attenuated as the animals grew older. These results document an essential role for STAT1 in FGF-mediated regulation of cell growth that is specific to the epiphyseal growth plate.
133 citations
TL;DR: Three genomic libraries were constructed using a mixture of DNA from Solanum phureja Juz.
Abstract: Three genomic libraries were constructed using a mixture of DNA from Solanum phureja Juz. & Buk., and S. chacoense Bitt. Two of the libraries were enriched for ATT and GT repeats (a 27-fold enrichm...
102 citations
TL;DR: The cultivars Ori, Idit, Zohar, and Zahov have been bred specifically for adaptation to the Mediteranean climate and were similar to Hermes, a standard chipstock cultivar commonly used in Israel.
Abstract: The cultivars Ori, Idit, Zohar, and Zahov have been bred specifically for adaptation to the Mediteranean climate: Ori and Idit are early tablestock cultivars, Idit is suited for “mini potatoes” (20 to 35 mm in diameter); Zohar is a midseason tablestock cultivai-, and Zahov is used as an early chipstock cultivar. The cultivars can be grown in either of the two main seasons in the Mediterranean region: the spring season (January through July) and the winter season (September through March). The cultivars have rapid emergence and early tuber set, they are tolerant to high temperatures and drought, and are not susceptible to external or internal defects. In field experiments, Idit yields were lower than the cultivar checks (Alpha, Nicola, or Desiree) in six of seven trials. However, the attractive appearance of the small oval tubers (20-35 mm in diameter) and the good aroma of the baked tubers are advantages. Yield of Ori and Zohar occasionally exceeded those of cultivar checks, and their yellowish skin, especially in sandy soils, is an advantage. Yields and tuber dry matter content of the early-maturing cultivar Zahov were similar to Hermes, a standard chipstock cultivar commonly used in Israel. The early maturation of Zahov is desirable to extend the harvest season.
12 citations
01 Jan 2001
TL;DR: Archeological remains and archives of the early Spanish occupation provide evidence that the potato was domesticated by the native population between 5,000 and 2,000 years prior to the Spanish discovery.
Abstract: The domestication of the potato (Solarium tuberosum L.) started millennia ago, around its center of evolution in South America. Many Solarium species, relatives of the domesticated potato grow wild in this area, mainly in the Andes of Peru and Bolivia. Archeological remains and archives of the early Spanish occupation provide evidence that the potato was domesticated by the native population between 5,000 and 2,000 years prior to the Spanish discovery.