Interference of mouse GATA-1 function by the glucocorticoid receptor at the level of the beta-globin gene and influence of GATA-1 on Friend leukemia virus (FLV) genome expression: Relationships to the inhibition of mouse erythroleukemia cell differentiation by glucocorticoids and to FLV erythrotropism.
Item
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Title
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Interference of mouse GATA-1 function by the glucocorticoid receptor at the level of the beta-globin gene and influence of GATA-1 on Friend leukemia virus (FLV) genome expression: Relationships to the inhibition of mouse erythroleukemia cell differentiation by glucocorticoids and to FLV erythrotropism.
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Identifier
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AAI9325078
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identifier
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9325078
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Creator
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Chang, Tai-Jay.
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Contributor
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Adviser: William Scher
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Date
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1993
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Cell | Biology, Genetics | Biology, Molecular
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Abstract
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Treatment of Friend leukemia virus (FLV)-infected mouse erythroleukemia (MEL) cells with hexamethylene bisacetamide (HMBA) induces a program of erythrodifferentiation as judged by an increase in the synthesis of globins and other erythroid-specific products. This induction can be inhibited by glucocorticoids, e.g., dexamethasone (DEX). All globin and other erythroid-specific genes tested contain GATA-response elements (GATA-RE) and can be transactivated by GATA-1, a major erythroid transcription factor. GATA-1 is highly expressed in erythroid cells, including MEL cells. A glucocorticoid receptor (GR) response element motif was noted near a GATA-RE motif in the promoter region of the mouse {dollar}\alpha\sb1{dollar}-globin, {dollar}\beta{dollar}-major and {dollar}\beta{dollar}-minor globin genes and in the FLV long terminal repeat (LTR) and, therefore, the possibility that the DEX-inhibition of induced MEL cell differentiation may involve effects of the GR on GATA-1 activity was investigated. Evidence obtained from transfection assays and DNA electrophoretic mobility shift assays indicates that the GR binds GATA-1 and interferes with its function prior to any interaction with DNA, and that the presence of a GRE near a GATA-RE augments the GR effect. The N-terminal 106-amino acid-domain of the GR was found to be essential for the effect possibly by binding to GATA-1. Since GATA-1 is autoregulatory, i.e., it has been shown by others to bind to its own promoter and upregulate its own transcription, the finding that activated GR can interfere with GATA-1 function may provide an explanation for the inhibition by glucocorticoids of the entire program of erythroid differentiation in MEL cells. That is, by interfering with GATA-1 function, the GR can not only inhibit the expression of erythroid structural genes, but also the expression of a regulatory gene, GATA-1 itself. In addition, it was shown that a GATA-RE in each of the {dollar}\beta{dollar}-globin promoters and in the FLV LTR responds to mouse GATA-1 in a functional transfection assay. FLV can infect many, if not all, cell types, but causes pathogenic effects primarily in cells of the erythroid lineage, and therefore is considered erythrotropic. The LTR response to GATA-1 appears to at least partially explain the mechanism of the erythrotropism of FLV.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
