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PubMed1990

A subpopulation of the avian erythroblastosis virus v-erbA protein, a member of the nuclear hormone receptor family, is glycosylated.

The v-erbA oncogene of avian erythroblastosis virus is derived from a cellular gene for a thyroid hormone (T4/T3 thyronine) receptor and encodes a DNA-binding protein found principally in the nucleus of the infected cell. I report here that a subpopulation of the v-erbA protein is glycosylated. The v-erbA protein, therefore, is another member of the newly recognized family of eucaryotic transcription factors and related polypeptides which are glycoproteins.

Alpharetrovirus↗

PubMed1990

Sequence-specific DNA binding by the v-erbA oncogene protein of avian erythroblastosis virus.

The v-erbA oncogene, a transduced copy of a thyroid hormone receptor, plays an important role in establishment of the transformed cell phenotype induced by avian erythroblastosis virus. The ability of thyroid hormone receptors to bind to specific sites on chromatin and to thereby modify the expression of adjacent target genes is a crucial element in their mechanism of action in the normal cell. The v-erbA protein also bound at high affinity to a set of DNA fragments recognized by the rat thyroid hormone receptor, but the relative affinity of the v-erbA protein for the different binding sites was distinct from that previously reported for the thyroid hormone receptors.

Alpharetrovirus↗

PubMed1991

Dissecting the activating mutations in v-erbB of avian erythroblastosis virus strain R.

The v-erbB oncogene isolated from the R (or ES4) strain of avian erythroblastosis virus is capable of inducing erythroleukemia and fibrosarcomas. This oncogene differs from the proto-oncogene c-erbB, the avian homolog of the epidermal growth factor receptor, by its lack of an intact ligand-binding domain as well as additional alterations in its cytoplasmic coding sequences. By contrast, the insertionally activated c-erbB, a variant oncogene, which encodes a product that also lacks the ligand-binding domain but is otherwise unaltered in its cytoplasmic coding sequences, is capable of inducing leukemia but cannot induce sarcomas. In this report, we show that the critical changes for activating the sarcomagenic potential displayed by v-erbB R are two point mutations within the tyrosine kinase domain and an internal deletion of 21 amino acids in the carboxyl-terminal regulatory domain. The removal of the carboxyl-terminal autophosphorylation sites is not obligatory. These activating mutations (Arg-263 to His, Ile-384 to Ser, and the deletion of residues 494 to 514), when introduced singly into the insertionally activated c-erbB, all dramatically increase fibroblast-transforming potential. Arg-263 resides near the highly conserved HRD motif of the kinase domain, and its mutation to His increases the autophosphorylation activity. The other two mutations do not alter the intrinsic kinase activity and presumably affect other aspects of the receptor involved in growth signaling. Therefore, the high transforming potential of v-erbB R is a consequence of synergism among multiple activating mutations.

Alpharetrovirus↗

PubMed1986

c-erbB activation in avian leukosis virus-induced erythroblastosis: multiple epidermal growth factor receptor mRNAs are generated by alternative RNA processing.

Avian leukosis virus-induced erythroblastosis results from the specific interruption of the host oncogene, c-erbB, by the insertion of an intact provirus. This insertion results in the expression of two size classes (3.6 and 7.0 kilobases [kb]) of truncated c-erbB transcripts which are initiated in the 5' long terminal repeat of the integrated provirus. Through sequence analysis of erbB cDNA clones we have previously shown that the 3.6-kb activated erbB mRNA contains portions of viral gag and env genes fused to c-erbB sequences (T.W. Nilsen, P.A. Maroney, R.G. Goodwin, F.M. Rottman, L.B. Crittenden, M.A. Raines, and H.-J. Kung, Cell 41:719-726, 1985). In this report we show that the 7-kb mRNA differs from the shorter activated c-erbB mRNA in the length of its 3' untranslated sequence such that the longer mRNA has an extremely long (4.3 kb) 3' untranslated sequence. Additionally, we demonstrate that activated c-erbB mRNA precursors can be processed by alternative splicing to yield mRNAs with viral gag sequences fused directly to c-erbB sequences. Finally, blot hybridization evidence suggests that the two size classes of activated c-erbB mRNA in erythroblastic tissue represent truncated versions of the two c-erbB mRNAs present in normal tissue.

Animals↗

PubMed1988

Genetic dissection of functional domains within the avian erythroblastosis virus v-erbA oncogene.

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.

Alpharetrovirus↗

PubMed2002

Idiopathic myelofibrosis with prominent postsplenectomy erythroblastosis terminating in acute myeloid transformation.

Idiopathic myelofibrosis is a myeloproliferative disease with poor prognosis and without sufficient therapy. Acute leukemic transformation occurs in 15% of patients. The authors report the case of a 63 year old myelofibrotic patient treated with splenectomy. During the clinical course they observed unusually prominent and persistent erythroblastosis in the peripherial blood. After a two years long, relatively stable period the disease terminated in acute myeloid leukemia.

Acute Disease↗

PubMed2002

Transferrin receptor hyperexpression in primary erythroblasts is lost on transformation by avian erythroblastosis virus.

In primary chicken erythroblasts (stem cell factor [SCF] erythroblasts), transferrin receptor (TfR) messenger RNA (mRNA) and protein were hyperexpressed as compared to nonerythroid chicken cell types. This erythroid-specific hyperexpression was abolished in transformed erythroblasts (HD3E22 cells) expressing the v-ErbA and v-ErbB oncogenes of avian erythroblastosis virus. TfR expression in HD3E22 cells could be modulated by changes in exogenous iron supply, whereas expression in SCF erythroblasts was not subject to iron regulation. Measurements of TfR mRNA half-life indicated that hyperexpression in SCF erythroblasts was due to a massive stabilization of transcripts even in the presence of high iron levels. Changes in mRNA binding activity of iron regulatory protein 1 (IRP1), the primary regulator of TfR mRNA stability in these cells, correlated well with TfR mRNA expression; IRP1 activity in HD3E22 cells and other nonerythroid cell types tested was iron dependent, whereas IRP1 activity in primary SCF erythroblasts could not be modulated by iron administration. Analysis of avian erythroblasts expressing v-ErbA alone indicated that v-ErbA was responsible for these transformation-specific alterations in the regulation of iron metabolism. In SCF erythroblasts high amounts of TfR were detected on the plasma membrane, but a large fraction was also located in early and late endosomal compartments, potentially concealing temporary iron stores from the IRP regulatory system. In contrast, TfR was almost exclusively located to the plasma membrane in HD3E22 cells. In summary, stabilization of TfR mRNA and redistribution of Fe-Tf/TfR complexes to late endosomal compartments may contribute to TfR hyperexpression in primary erythroblasts, effects that are lost on leukemic transformation.

Alpharetrovirus↗

PubMed1985

The use of anti-synthetic peptide antibodies to study the v-erb B protein from chicken and rat cells transformed by avian erythroblastosis virus.

Two site-specific anti-peptide antisera have been produced that efficiently recognize the native form of the v-erb B protein from avian erythroblastosis virus (AEV)-infected chicken erythroblasts and fibroblasts, and from AEV-transformed mammalian cells. Since the antibodies were generated against synthetic sequences, the immunoprecipitations could be performed in the presence or absence of immunizing peptide, permitting the specifically precipitated proteins to be identified from background non-specifically adsorbed proteins. We confirmed that immobilized v-erb B protein from cell lysates of unlabelled AEV-infected chicken erythroblasts became labelled upon incubation with [gamma-32P]ATP. In addition we demonstrated for the first time that v-erb B from mammalian cells became labelled under the same conditions. These results suggest that the v-erb B protein may possess intrinsic kinase activity. The reagents described should permit further investigations as to whether this activity plays a role in maintaining cellular transformation.

Adenosine Triphosphate↗

PubMedDate not supplied

In vitro transformation of chicken bone marrow cells with avian erythroblastosis virus.

An in vitro transformation of bone marrow cells has been demonstrated for two strains of avian erythroblastosis virus (AEV-R and AEV-ES4). The transformed cells were indistinguishable from in vivo transformed erythroblasts in morphology and staining characteristics and could be propagated to large numbers. The transformation efficiency could be greatly increased by the addition of dimethylsulfoxide (DMSO). The number of foci appearing in the presence of DMSO was proportional to the virus concentration.

Alpharetrovirus↗

PubMed1976

[Malignant erythroblastosis].

In form of a survey the clinical picture of the malignant erythroblastosis is described. Apart from notes concerning the etiology and pathogenesis symptomatology and differential diagnosis are of special importance. The most important morphological and cytochemical changes are demonstrated with the help of micropictures.

Anemia, Hemolytic↗

PubMed1992

Avian erythroblastosis: a model system to study oncogene co-operation in leukemia.

Avian erythroblastosis virus, AEV-ES4, provides an ideal in vitro system to study oncogene co-operation in the development of erythroid leukaemias in chickens. Two oncogenes that use distinct signal transduction pathways have been identified; these act to produce a highly malignant phenotype and are an oncogenic version of a plasma membrane growth factor receptor that regulates haematopoietic progenitor self renewal and a mutated version of a transcription factor that suppresses specific gene expression. These two diverse types of oncogenes act together to generate a more malignant phenotype than would be expected merely from a summation of the individual oncogene effects. The aspects of normal growth control and the regulation of differentiation, which are altered in this system to generate the leukaemic phenotype, include changes in the balance between proliferation versus maturation, altered expression of differentiation genes and changes in growth factor responsiveness. These are exactly those features that are altered in human leukaemias. Thus, the avian leukaemia virus model has taught us important lessons that will help us to understand the basic molecular mechanisms that give rise to human leukaemia.

Alpharetrovirus↗

PubMed1991

Induction of differentiation of avian erythroblastosis virus-transformed erythroblasts by the protein kinase inhibitor H7: analysis of the transcription factor EF1.

The protein kinase inhibitor H7 [1-5(isoquinolinesulfonyl-2-methylpiperazine)] together with a temperature shift to 42 degrees C was found to reproducibly and efficiently induce differentiation of avian erythroblasts transformed with the avian erythroblastosis virus containing v-erbA and a temperature-sensitive v-erbB oncogene. Although a temperature shift to 42 degrees C without H7 results in some elevation of globin transcripts, much higher levels of transcripts accrue when cells are incubated at 42 degrees C with H7; under such conditions, 50-70% of the cells become benzidine positive. In order to investigate the mechanism by which the differentiation occurs, we have characterized and analyzed the levels of the erythroid transcription factor EF1, originally described as a factor binding to the beta H-globin promoter. Protein sequencing of EF1 shows that it is identical to the factor Eryf1. Using a peptide antibody and DNA-binding assays, we demonstrate that EF1 is present at high levels in the nucleus of undifferentiated HD3 cells, and, although there may be a small change when the cells are shifted to 42 degrees C, incubation of the cells with H7 at 42 degrees C does not result in a further elevation commensurate with the high levels of globin transcripts. It is concluded that v-erbA and v-erbB do not repress differentiation by limiting the levels of EF1.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1992

Cellular and molecular mechanisms of renal carcinogenesis induced by avian erythroblastosis virus.

Besides erythroleukemias and sarcomas, avian erythroblastosis virus strain ES4 (AEV-ES4) induces renal adenocarcinomas (RCas) in chickens. To search for the cells of origin and the mechanism of the development of RCas, we investigated the RCas produced by td359AEV, a mutant of AEV-ES4 which lacks a leukemogenic effect, but which is sarcomagenic. Spindle cell sarcomas in various organs and RCas developed in a high number of chickens inoculated with td359AEV. RCas were tubulo-cystopapillary structures of basophilic cells and originated only from differentiated principal cells (PCs) of the renal collecting duct system. The origin of tumors from PCs was indicated by connections of tumor epithelium to segments of the collecting duct system, including connecting tubules and cortical and medullary collecting ducts. Tumor cells showed typical mucopolysaccharide-containing vacuoles which are characteristic of chicken PCs. Viral particles were observed throughout the kidney. Moreover, the highest numbers of particles as well as budding-images of them were seen (apart from tumor cells) in podocytes and distal tubule cells which did not undergo neoplastic change. The susceptibility of PCs to undergo neoplastic transformation could not be related to a particular activation state of the erbB gene, in view of the fact that cerbB expression was detected by in situ hybridization in the epithelium lining the Bowmann's capsule and the entire renal tubule system. From data of Northern blot and in situ hybridization techniques, it was suggested that the neoplastic transformation of PCs was elicited by overexpression of the v-erbB oncogene, a feature of tumor cells already detected in renal tubules lined by basophilic proliferating cells, the first stages of renal carcinogenesis induced by td359AEV. According to Southern blot analysis, td359AEV proviruses were randomly inserted in tumor DNAs and the RCas were polyclonal in nature.

Alpharetrovirus↗

PubMed1978

A complement fixing antigen in the livers of birds infected with an avian leukovirus (erythroblastosis virus).

Extracts of erythroblastosis affected livers from which much of the structural protein had been removed were prepared by acid denaturation. These extracts contained complement fixing "soluble" antigen in a form which was not associated with viral or subviral particles. Ultracentrifugation can be of assistance in separating complement fixation activity from contaminating material in these extracts.

Alpharetrovirus↗

PubMed1989

Increase in ribosomal protein S6 phosphorylation is due to v-erbB-transforming activity and not to v-erbA mitogenic activity in avian erythroblastosis virus-infected chicken embryo fibroblasts.

Avian erythroblastosis virus (AEV-ES4), a transforming avian retrovirus, transforms chicken embryo fibroblasts (CEFs) in culture and induces the maintenance of ribosomal protein S6 phosphorylation in the absence of serum. This effect is less pronounced after AEV-ES4 transformation than after transformation by Rous sarcoma virus (PR-RSV A). However, our results indicate that the two viruses induce an activation of the same S6 phosphokinase, as evidenced by the identity of S6 phosphopeptides and phosphoaminoacids in the two cases. Moreover this activation is performed through a protein kinase C-independent pathway. Expression of the v-erbA oncogene alone, which enhances the growth potential of CEFs, is not able to maintain S6 phosphorylation either in the absence of serum or in the presence of low serum concentration (0.5%). Expression of the v-erbB oncogene alone is responsible for all these AEV-ES4-induced effects. Furthermore, the maintenance of S6 phosphorylation in the absence of serum might be correlated with the degree of transformation of AEV-ES4-infected CEFs. These results show that S6 phosphorylation is one of the biochemical mechanisms deregulated by v-erbB expression and is involved in the transformation process.

Alpharetrovirus↗

PubMed1987

Common site of mutation in the erbB gene of avian erythroblastosis virus mutants that are temperature sensitive for transformation.

The genome of the avian erythroblastosis virus temperature sensitive mutant ts34 was cloned from a cell line that was shown to contain a single integrated copy of the virus. The mutation was localized to the v-erbB gene by making chimeric viruses between the mutant genome and that of wildtype. Sequencing of the mutant v-erbB gene revealed a single amino acid change of a histidine to an aspartate residue at a position equivalent to amino-acid 826 of the human epidermal growth factor receptor. Interestingly this is the identical mutation to that recently reported for another temperature sensitive mutant ts167, indicating that this may be a hot spot for mutations in the v-erbB gene that give rise to ts transformation mutants. In addition, the different biological phenotypes of ts34 and ts167 are suggested to be due to an additional mutation in v-erbA in ts167.

Alpharetrovirus↗

PubMed1985

Phosphorylation of the erbB gene product from an avian erythroblastosis virus-transformed chick fibroblast cell line.

Polyclonal antiserum prepared against the human epidermal growth factor receptor immunoprecipitated four proteins of Mr = 66,000, 68,000, 74,000, and 82,000 from avian erythroblastosis virus-transformed chick embryo fibroblasts (cell line AEV-C23) which seemed to be related to the erbB gene product. The Mr = 66,000 and 68,000 proteins chased into the Mr = 74,000 and 82,000 proteins in pulse-chase experiments. The Mr = 68,000 and 82,000 proteins were found to be phosphorylated primarily on serine and threonine residues and contained minor amounts of phosphotyrosine. Tryptic peptide analysis of these phosphoproteins revealed several major peptides, and treatment of cells with the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate resulted in the appearance of an additional phosphopeptide. 12-O-Tetradecanoyl-phorbol-13-acetate also inhibited growth of AEV-C23 cells in soft agar and in monolayer culture. In vitro phosphorylation of Mr = 68,000 and 74,000 proteins in immunoprecipitates occurred on tyrosine with lesser amounts of phosphoserine and phosphothreonine detected.

Alpharetrovirus↗

PubMed1986

[Mitogenic action of factors secreted by avian erythroblastosis virus transformed cells].

We describe here the capacity of erythroid LSCC HD3 cells, transformed with a ts mutant of avian erythroblastosis virus, to grow in a chemically defined medium without serum at 36 degrees C, but not at 41 degrees C. At this latter temperature the activity of v-erbB oncogene is suppressed. However, cell growth at 41 degrees C could take place either by addition of the medium derived from LSCC HD3 cells grown at 36 degrees C (conditioned medium), or by addition of fetal calf serum. These results show that LSCC HD3 cells, maintained under conditions in which the v-erbB oncogene is active, secrete growth factor(s) which exhibit a mitogenic effect similar to that observed with calf serum.

Alpharetrovirus↗