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Use of avian retroviral vectors to introduce transcriptional regulators into mammalian cells for analyses of tumor maintenance.
Pao W, Klimstra DS, Fisher GH, Varmus HE
(2003) Proc Natl Acad Sci U S A 100: 8764-9
MeSH Terms: Animals, Avian Leukosis Virus, Avian Proteins, Doxycycline, Genes, ras, Genetic Complementation Test, Genetic Vectors, Mice, Mice, Knockout, Mice, Nude, Mice, Transgenic, Neoplasms, Experimental, Receptors, Virus, Trans-Activators
Show Abstract · Added March 24, 2014
A key issue in cancer biology is whether genetic lesions involved in tumor initiation or progression are required for tumor maintenance. This question can be addressed with mouse models that conditionally express oncogenic transgenes, i.e., under the control of tetracycline (tet)-dependent transcriptional regulators. We have developed a system for studying tumor maintenance by using avian retroviral [i.e., replication-competent avian leukosis virus long terminal repeat with splice acceptor (RCAS)] vectors to deliver the reverse tet transcriptional transactivator (rtTA) gene to somatic mammalian cells. rtTA can regulate any transgene in which the protein coding sequence is preceded by a tet-operator (tet-o); RCAS viruses infect only cells engineered to express ectopically the avian retroviral receptor, TVA. One vector, RCAS-rtTA-IRES-GFP, also encodes GFP to identify infected cells. Infection of cells from beta-actin TVA transgenic mice with this vector permits efficient regulation of tet-responsive transgenes. Sarcomas arise when p53-deficient murine embryonic fibroblasts carrying beta-actin TVA and tet-o-K-ras4bG12D transgenes are infected with RCAS-rtTA-IRES-GFP and introduced into nude mice treated with the tet analog, doxycycline (dox); when dox is withdrawn, K-ras4bG12D levels fall, cells undergo apoptosis, and tumors regress. Regression can be prevented by means of a genetic complementation assay in which tumors are superinfected before dox withdrawal with other RCAS viruses, such as those carrying an active allele of K-ras. Many TVA and tet-regulated transgenic mice have been generated; thus, this method for somatic cell-specific and temporally controlled gene expression may have broad applications for the study of oncogenesis and tumor maintenance, as well as other cell functions and development.
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14 MeSH Terms
Site-specific mutagenesis of avian erythroblastosis virus: v-erb-A is not required for transformation of fibroblasts.
Sealy L, Moscovici G, Moscovici C, Bishop JM
(1983) Virology 130: 179-94
MeSH Terms: Alpharetrovirus, Animals, Avian Leukosis, Avian Leukosis Virus, Cell Transformation, Viral, Chick Embryo, Chromosome Deletion, Cloning, Molecular, Fibroblasts, Genes, Viral, Mutation, Oncogenes, Viral Proteins, Virus Replication
Show Abstract · Added March 5, 2014
Avian erythroblastosis virus (AEV) is an acutely transforming retrovirus whose putative oncogenes (v-erb-A and v-erb-B) encode the proteins P74gag-erb-A and P61-68erb-B. The existence of these two gene products has prompted the question of whether one or both proteins are required in the transformation of erythroblasts and fibroblasts by AEV. In the accompanying manuscript, we describe the use of site-specific mutagenesis to generate mutants of AEV unable to synthesize P61-68erb-B. Here we present our analysis of the oncogenic potential of an AEV mutant unable to synthesize P74gag-erb-A due to a large deletion encompassing both gag and v-erb-A sequences. The erb-A-mutant retrovirus propagated quite poorly on fibroblasts in culture; however, fibroblasts harboring the erb-A mutant genome were transformed in the absence of P74gag-erb-A expression. The mutant virus failed to induce erythroleukemias in chickens, but the validity of this finding is compromised by the poor replicative capacity of the mutant. The results presented in this and the preceding manuscript indicate that P61-68erb-B is both necessary and sufficient for neoplastic transformation of fibroblasts by AEV; by contrast, a role for p74gag-erb-A in leukemogenesis by AEV has not yet been rigorously excluded.
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The product of the avian erythroblastosis virus erbB locus is a glycoprotein.
Privalsky ML, Sealy L, Bishop JM, McGrath JP, Levinson AD
(1983) Cell 32: 1257-67
MeSH Terms: Alpharetrovirus, Animals, Avian Leukosis Virus, Cell Transformation, Viral, Cells, Cultured, Chickens, Erythroblasts, Genes, Viral, Glycoproteins, Molecular Weight, Oncogenes, Protein Processing, Post-Translational, Tunicamycin, Viral Proteins
Show Abstract · Added March 5, 2014
Avian erythroblastosis virus (AEV) induces both erythroblastosis and fibrosarcomas in susceptible birds. A locus, v-erbB, within the viral genome has been implicated in AEV-mediated oncogenesis. We report here the detection and partial characterization of the protein product of the v-erbB oncogene in AEV-transformed cells. We obtained the antisera necessary for our analysis by expressing a portion of the molecularly cloned v-erbB locus in Escherichia coli and immunizing rabbits with the resulting bacterial erbB polypeptide. Antisera directed against the bacterial polypeptide reacted with v-erbB proteins obtained from virus-infected avian cells. By three criteria--tunicamycin inhibition, lectin binding and metabolic labeling with radioactive sugar precursors--the product of the v-erbB gene appears to be a glycoprotein.
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14 MeSH Terms
Site-specific mutagenesis of avian erythroblastosis virus: erb-B is required for oncogenicity.
Sealy L, Privalsky ML, Moscovici G, Moscovici C, Bishop JM
(1983) Virology 130: 155-78
MeSH Terms: Alpharetrovirus, Animals, Avian Leukosis, Avian Leukosis Virus, Cell Transformation, Viral, Chick Embryo, Chromosome Deletion, Cloning, Molecular, Fibroblasts, Genes, Viral, Mutation, Oncogenes, RNA-Directed DNA Polymerase, Transfection
Show Abstract · Added March 5, 2014
Avian erythroblastosis virus (AEV) induces both erythroblastosis and fibrosarcomas in susceptible birds. Two domains within its replication-defective genome, erb-A and erb-B, have been implicated in AEV-mediated oncogenesis. An efficient transfection system for generating infectious, transforming virus from molecular clones of AEV and RAV-1 (helper virus) was combined with the techniques of site-specific mutagenesis to investigate the contribution of erb-B to the two forms of oncogenesis induced by AEV. Deletion and frameshift mutations were constructed in the erb-B locus of cloned AEV DNA in vitro. Infectious retroviruses harboring these mutations were recovered and their ability to transform fibroblasts in vitro or induce erythroleukemia in vivo was assessed. The presence of mutant viral genomes in chick embryo fibroblasts or erythroblasts of infected birds was confirmed by suitable biochemical analyses. Expression of viral genes in cells infected with AEV mutants was examined by immunoprecipitation with antisera to erb-A and erb-B proteins. It was found that the product of erb-B is necessary for transformation of fibroblasts and induction of erythroblastosis by AEV, although a small portion of this protein at the carboxy terminus is dispensable.
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14 MeSH Terms