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1.
The avian erythroblastosis virus v-erbA oncogene is imprecisely derived from a cellular gene (c-erbA) encoding a thyroid hormone receptor: the v-erbA protein has sustained both small terminal deletions and internal amino acid sequence changes relative to c-erbA. We report here that one of these missense differences between v- and c-erbA proteins, located in a zinc finger DNA binding domain, has dramatic effects on the biological activities of the encoded protein. Back mutation of the viral coding sequence to resemble c-erbA at this site severely impairs erythroid transformation and produces subtle changes in DNA binding by the encoded protein, suggesting that differences in DNA binding by the viral and cellular proteins may be involved in the activation of v-erbA as an oncogene.  相似文献   

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M Sharif  M L Privalsky 《Cell》1991,66(5):885-893
The v-erbA oncoprotein of avian erythroblastosis virus is an aberrant version of a thyroid hormone receptor and functions in neoplasia by blocking erythroid differentiation and by modifying the growth properties of fibroblasts. v-erbA has been proposed to represent a novel dominant negative oncogene, acting in the cancer cell by interfering with the actions of its normal cell homologs, the thyroid hormone receptors. We report here that v-erbA can actually interfere with the actions of a variety of members of the steroid/retinoid receptor family and that the ability of v-erbA to act in neoplasia best correlates not with suppression of c-erbA action, but with interference with the retinoic acid receptor response. We suggest that v-erbA may act in neoplasia by promiscuously interfering with a retinoid-mediated differentiation process.  相似文献   

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The c-erbA proto-oncogenes encode nuclear receptors for thyroid hormone (T3), a hormone intimately involved in mammalian brain maturation. To study thyroid hormone receptor (TR) action on neuronal cells in vitro, we expressed the chicken c-erbA/TR alpha-1 as well as its oncogenic variant v-erbA in the adrenal medulla progenitor cell line PC12. In the absence of T3, exogenous TR alpha-1 inhibits NGF-induced neuronal differentiation and represses neuron-specific gene expression. In contrast, TR alpha-1 allows normal differentiation and neuronal gene expression to occur in the presence of T3. Finally, TR alpha-1- expressing cells become NGF-responsive for proliferation when T3 is absent, but NGF-dependent for survival in presence of T3. A similar differentiation induction by NGF plus T3 was observed in a central nervous system-derived neuronal cell line (E 18) expressing exogenous TR alpha-1. Together with the finding that TR alpha-1 constitutively blocked dexamethasone-induced differentiation of PC12 cells into the chromaffin pathway, these results suggest that TR alpha-1 plays an important role in regulating commitment and maturation of neuronal progenitors. In contrast, the v-erbA oncogene, a mutated, oncogenic version of TR alpha-1, partially but constitutively inhibited NGF- induced neuronal differentiation of PC12 cells and potentiated dexamethasone-induced chromaffin differentiation, giving rise to an aberrant "interlineage" cell phenotype.  相似文献   

5.
The avian erythroblastosis virus v-erbA locus potentiates the oncogenic transformation of erythroid and fibroblast cells and is derived from a host cell gene encoding a thyroid hormone receptor. We report here the use of site-directed mutagenesis to identify and characterize functional domains within the v-erbA protein. Genetic lesions introduced into a putative hinge region or at the extreme C-terminus of the v-erbA coding domain had no significant effect on the biological activity of this polypeptide. In contrast, mutations introduced within the cysteine-lysine-arginine-rich center of the v-erbA coding region, a DNA-binding domain in the thyroid and steroid hormone receptors, abolished or severely compromised the ability of the viral protein to function. Our results suggest that the mechanism of action of the v-erbA protein in establishing the neoplastic phenotype is closely related to its ability to interact with DNA, presumably thereby altering expression of host target genes by either mimicking or interfering with the action of the normal c-erbA gene product.  相似文献   

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K Damm  H Beug  T Graf    B Vennstrm 《The EMBO journal》1987,6(2):375-382
We have characterized the v-erbA and v-erbB oncogenes of td359, a transformation-defective mutant of avian erythroblastosis virus (AEV) unable to transform erythroblasts, and the revertant r12, obtained after in vivo passage of the mutant. Molecular cloning, sequencing, construction of chimeric viruses and testing of their oncogenic capacities revealed that both oncogenes of td359 are mutated and biologically defective. The r12 virus, although still containing a mutant v-erbB gene, recovered its erythroid transforming potential by acquiring a highly active gag-erbA gene. These results demonstrate that two co-operating oncogenes, an active v-erbA and a defective v-erbB, can transform a cell type not transformed by either oncogene alone. Furthermore, a single amino acid substitution inactivated the td359 v-erbA protein and we show that its reversion led to the reactivation of the protein. This lesion is located in the same region as several previously described inactivating mutations of glucocorticoid receptors, suggesting that the structure/function relationship of the virally transduced form of the c-erbA/thyroid hormone receptor is closely similar to that of steroid hormone receptors.  相似文献   

9.
V-erbA is thought to be an antagonist of thyroid hormone receptor (T3R) function. Here we show that unliganded T3R, but not v-erbA, suppresses retinoic acid (RA)-dependent induction of the RAR-beta 2 promoter by competing for the common dimerization partner, the retinoid X receptor (RXR). Firstly, T3R suppression can be alleviated by co-transfection of RXR. Secondly, T3R, but not v-erbA, competes with RAR for RXR and causes the dissociation of a preformed RAR/RXR-RARE ternary complex in vitro. A single point mutation located in the dimerization interface of v-erbA (Pro349 to Ser) abolishes the transdominant phenotype when introduced at the respective position in T3R. The hypertransforming v-erbA variant r12, in which this mutation is reversed (Ser349 to Pro) suppresses RA-induced differentiation in chicken erythroid progenitors, while v-erbA does not. Our data thus suggest that unliganded T3R and v-erbA act as dominant suppressors through mechanistically distinct pathways.  相似文献   

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