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Mutant
About: Mutant is a research topic. Over the lifetime, 74520 publications have been published within this topic receiving 3477079 citations.
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TL;DR: The decreased frequency of recovery of the EBNA-3A mutation, the requirement for transformation-defective EBV coinfection, and the inability to maintain theEBNA- 3A mutation indicate that EBNA -3A is essential or critical for lymphocyte growth transformation and that the EB NA-3C mutation has a partial dominant negative effect.
Abstract: Recombinant Epstein-Barr viruses (EBV) with a translation termination codon mutation inserted into the nuclear protein 3A (EBNA-3A) or 3C (EBNA-3C) open reading frame were generated by second-site homologous recombination. These mutant viruses were used to infect primary B lymphocytes to assess the requirement of EBNA-3A or -3C for growth transformation. The frequency of obtaining transformants infected with a wild-type EBNA-3A recombinant EBV was 10 to 15%. In contrast, the frequency of obtaining transformants infected with a mutant EBNA-3A recombinant EBV was only 1.4% (9 mutants in 627 transformants analyzed). Transformants infected with mutant EBNA-3A recombinant virus could be obtained only by coinfection with another transformation-defective EBV which provided wild-type EBNA-3A in trans. Cells infected with mutant EBNA-3A recombinant virus lost the EBNA-3A mutation with expansion of the culture. The decreased frequency of recovery of the EBNA-3A mutation, the requirement for transformation-defective EBV coinfection, and the inability to maintain the EBNA-3A mutation indicate that EBNA-3A is essential or critical for lymphocyte growth transformation and that the EBNA-3A mutation has a partial dominant negative effect. Five transformants infected with mutant EBNA-3C recombinant virus EBV were also identified and expanded. All five also required wild-type EBNA-3C in trans. Serial passage of the mutant recombinant virus into primary B lymphocytes resulted in transformants only when wild-type EBNA-3C was provided in trans by coinfection with a transformation-defective EBV carrying a wild-type EBNA-3C gene. A secondary recombinant virus in which the mutated EBNA-3C gene was replaced by wild-type EBNA-3C was able to transform B lymphocytes. Thus, EBNA-3C is also essential or critical for primary B-lymphocyte growth transformation.
414 citations
TL;DR: Diverse toxic lipophilic and electrophilic metabolites, disposed of by phase 1 and phase 2 drug metabolism, may be the major determinants of the molecular damage that causes aging.
414 citations
TL;DR: E protein IC activity represents a new determinant for SARS-CoV virulence, and is associated with reduced edema accumulation, the major determinant of acute respiratory distress syndrome (ARDS) leading to death.
Abstract: Deletion of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) envelope (E) gene attenuates the virus. E gene encodes a small multifunctional protein that possesses ion channel (IC) activity, an important function in virus-host interaction. To test the contribution of E protein IC activity in virus pathogenesis, two recombinant mouse-adapted SARS-CoVs, each containing one single amino acid mutation that suppressed ion conductivity, were engineered. After serial infections, mutant viruses, in general, incorporated compensatory mutations within E gene that rendered active ion channels. Furthermore, IC activity conferred better fitness in competition assays, suggesting that ion conductivity represents an advantage for the virus. Interestingly, mice infected with viruses displaying E protein IC activity, either with the wild-type E protein sequence or with the revertants that restored ion transport, rapidly lost weight and died. In contrast, mice infected with mutants lacking IC activity, which did not incorporate mutations within E gene during the experiment, recovered from disease and most survived. Knocking down E protein IC activity did not significantly affect virus growth in infected mice but decreased edema accumulation, the major determinant of acute respiratory distress syndrome (ARDS) leading to death. Reduced edema correlated with lung epithelia integrity and proper localization of Na+/K+ ATPase, which participates in edema resolution. Levels of inflammasome-activated IL-1β were reduced in the lung airways of the animals infected with viruses lacking E protein IC activity, indicating that E protein IC function is required for inflammasome activation. Reduction of IL-1β was accompanied by diminished amounts of TNF and IL-6 in the absence of E protein ion conductivity. All these key cytokines promote the progression of lung damage and ARDS pathology. In conclusion, E protein IC activity represents a new determinant for SARS-CoV virulence.
413 citations
TL;DR: It is reported that HY5 is constitutively nuclear localized and is involved in light regulation of transcriptional activity of the promoters containing the G-box, a well-characterized light-responsive element (LRE).
Abstract: The Arabidopsis HY5 gene has been defined genetically as a positive regulator of photomorphogenesis and recently has been shown to encode a basic leucine zipper type of transcription factor. Here, we report that HY5 is constitutively nuclear localized and is involved in light regulation of transcriptional activity of the promoters containing the G-box, a well-characterized light-responsive element (LRE). In vitro DNA binding studies suggested that HY5 can bind specifically to the G-box DNA sequences but not to any of the other LREs present in the light-responsive promoters examined. High-irradiance light activation of two synthetic promoters containing either the consensus G-box alone or the G-box combined with the GATA motif (another LRE) and the native Arabidopsis ribulose bisphosphate carboxylase small subunit gene RBCS-1A promoter, which has an essential copy of the G-box, was significantly compromised in the hy5 mutant. The hy5 mutation's effect on the high-irradiance light activation of gene expression was observed in both photosynthetic and nonphotosynthetic tissues. Furthermore, the characteristic phytochrome-mediated red light- and far-red light-reversible low-fluence induction of the G-box-containing promoters was diminished specifically in hy5 plants. These results suggest that HY5 may interact directly with the G-box in the promoters of light-inducible genes to mediate light-controlled transcriptional activity.
413 citations
TL;DR: Genes with human orthologs were overrepresented in their screens, suggesting that the authors may have discovered conserved and nonoverlapping sets of cell-autonomous genes and pathways that are relevant to Huntington's disease and Parkinson's disease.
Abstract: Genome-wide screens were performed in yeast to identify genes that enhance the toxicity of a mutant huntingtin fragment or of alpha-synuclein. Of 4850 haploid mutants containing deletions of nonessential genes, 52 were identified that were sensitive to a mutant huntingtin fragment, 86 that were sensitive to alpha-synuclein, and only one mutant that was sensitive to both. Genes that enhanced toxicity of the mutant huntingtin fragment clustered in the functionally related cellular processes of response to stress, protein folding, and ubiquitin-dependent protein catabolism, whereas genes that modified alpha-synuclein toxicity clustered in the processes of lipid metabolism and vesicle-mediated transport. Genes with human orthologs were overrepresented in our screens, suggesting that we may have discovered conserved and nonoverlapping sets of cell-autonomous genes and pathways that are relevant to Huntington's disease and Parkinson's disease.
413 citations