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PubMed1985

c-erbB activation in ALV-induced erythroblastosis: novel RNA processing and promoter insertion result in expression of an amino-truncated EGF receptor.

ALV-induced erythroblastosis results from the specific interruption of the host oncogene, c-erbB, by the insertion of an intact provirus. Integrated proviruses are oriented in the same transcriptional direction as c-erbB, and expression of truncated c-erbB transcripts is observed. Evidence, including sequence analysis of cDNA clones, indicates that transcription of truncated c-erbB mRNA is initiated in the 5' LTR of the integrated provirus. This transcript is processed through a series of remarkable splicing reactions to yield viral gag and env sequences fused to erbB sequences. These results establish a novel pathway of promoter insertion oncogenesis that stands in contrast to the pathways used in the activation of c-myc in B lymphomas.

Animals↗

PubMedDate not supplied

Tripartite structure of the avian erythroblastosis virus E26 transforming gene.

Only two avian oncogenic viruses specifically cause acute leukaemias yet do not transform chicken fibroblasts in culture: E26, which causes erythroblastosis and a low level of concomitant myeloblastosis in chickens, and avian myeloblastosis virus (AMV), which causes myeloblastosis exclusively. Both viruses are replication-defective and share a sequence termed myb (also known as amv) which is unrelated to essential virion genes and is therefore thought to be part of the transforming onc genes of these viruses. However, the genetic structure of the two viruses differs. E26 has a genomic RNA of 5.7 kilobases (kb) and encodes a 135,000 molecular weight gag-related protein (p135) with probable transforming function. We show here by in vitro translation that the 5.7-kb E26 RNA directs the synthesis of p135. Oligonucleotide analysis indicates that E26 RNA contains an internal 0.8-kb subset of the 1.2-kb AMV-related sequence (mybA), termed mybE. A 2.46-kb molecular clone prepared from cDNA transcribed in vitro from E26 RNA contained an E26 transformation-specific (ets) sequence flanked by mybE and an env-related sequence. A complete DNA sequence of this clone indicates that the 1.5-kb ets sequence extends the open reading frame of mybE for 491 amino acids. Thus, the p135 gene of E26 is a genetic hybrid of three distinct elements, approximately 1.2 kb derived from the 5' region of the retroviral gag gene, mybE and the ets sequence, linked in the order 5'-delta gag-mybE-ets-3'. The myeloid leukaemogenicity shared by E26 and AMV correlates with the common myb sequence, while the distinct erythroid leukaemogenicity of E26 correlates with ets and the E26-specific linkage of myb to delta gag.

Amino Acid Sequence↗

PubMed1978

Post-transcriptional suppression of globin gene expression in cells transformed by avian erythroblastosis virus.

Cells transformed by avian erythroblastosis virus were grown in vitro for up to 5 months. After a few days in culture, synthesis of hemoglobin was undetectable and could not be induced by dimethyl sulfoxide. As shown by globin cDNA hybridization to nuclear and cytoplasmic RNA carried to Crot values of 10(5) moles of nucleotide per liter X sec, globin genes in these cells are transcribed into pre-mRNA, but no trace of globin mRNA appears in the cytoplasm. The implications of this observation for schemes of post-transcriptional regulations and viral transformation are discussed.

Alpharetrovirus↗

PubMed1980

Mutant of avian erythroblastosis virus defective for erythroblast transformation: deletion in the erb portion of p75 suggests function of the protein in leukemogenesis.

Previous studies have shown that td359 AEV, a mutant of avian erythroblastosis virus (AEV), is unable to transform erythroblasts in vitro or in vivo but is capable of transforming fibroblasts in vitro and of causing sarcomas in chicks. In this paper we show that the mutant synthesizes a gag-gene related protein (delta p75) which is about 1000 daltons smaller than the protein, p75, induced by wild-type AEV. The mutant protein lacks 3 of the approximately 53 lysine-arginine tryptic peptides resolved in p75 and also contains an additional peptide. By cleavage of delta p75 with p15 protease and analysis of the fragments for size and peptide composition, the deletion in delta p75 could be located in the non-gag region of the molecule. In contrast, with p40 AEV, a second AEV-specific protein synthesized in in vitro translation experiments, there is no change in size of translation products obtained from td359 AEV RNA. Our data provide direct evidence that p75 is required for erythroblast transformation.

Alpharetrovirus↗

PubMed1980

Comparative tryptic peptide mapping studies suggest a role in cell transformation for the gag-related protein of avian erythroblastosis virus and avian myelocytomatosis virus strains CMII and MC29.

The gag-related proteins found in cells transformed by avian erythroblastosis virus (AEV) and the avian myelocytomatosis viruses MC29 and CMII have been compared by tryptic peptide fingerprinting. A comparison of the methionine-containing tryptic peptides of the AEV 75-kilodalton protein, the CMII 90-kilodalton protein, and the MC29 110-kilodalton protein with the gag gene product Pr76 of their naturally occurring helper leukemia viruses enabled us to distinguish those peptides related to the gag gene from the non-gag-related peptides. The 12 non-gag peptides found in the AEV 75-kilodalton protein were unique to this protein and not found in the MC29 110-kilodalton or CMII 90-kilodalton proteins. In contrast, the MC29 110-kilodalton protein shared two methionine-containing non-gag tryptic peptides with the CMII 90-kilodalton protein. When these experiments were repeated with [14C]lysine and [14C]arginine as the labeled amino acids, the MC29 110-kilodalton protein and the CMII 90-kilodalton protein were found to share 30 out of approximately 40 non-gag-related peptides. These results demonstrate that viruses with a similar transformation spectrum synthesize related proteins and suggest that the gag-related proteins represent the transforming proteins of the replication-defective avian leukemia viruses.

Alpharetrovirus↗

PubMed1985

The ets sequence from the transforming gene of avian erythroblastosis virus, E26, has unique domains on human chromosomes 11 and 21: both loci are transcriptionally active.

Human DNA segments homologous to the ets region from the transforming gene of avian erythroblastosis virus, E26, were molecularly cloned and shown to be closely related to the viral equivalent by hybridization and partial sequence analysis. The transforming gene of E26 has a tripartite origin with the structure delta gag [1.2 kilobases (kb) from the viral gag gene]-myb(0.9 kb from the chicken myb gene)-ets (1.6 kb from the chicken ets gene). Human ets DNA is located on two distinct human chromosomes. The human ets-1 locus on chromosome 11 encodes a single mRNA of 6.8 kb; the second locus, ets-2 on chromosome 21, encodes three mRNAs of 4.7, 3.2, and 2.7 kb. The ets-related sequences of human DNA on chromosomes 11 and 21 are discontiguous, except for a small overlap region encoding 14 amino acids, where 12 are conserved between these two loci. By contrast, the chicken homolog has contiguous ets-1 and ets-2 sequences and is primarily expressed in normal chicken cells as a single 7.5-kb mRNA. We conclude that the ets sequence shared by the virus, the chicken, and humans is likely to contain at least two dissociable functional domains, ets-1 and ets-2. Thus, the tripartite transforming gene of E26 includes four distinct domains that may be functionally relevant for the transforming function of the virus (delta gag, myb, ets-1, and ets-2).

Alpharetrovirus↗

PubMed1985

c-erbB activation in avian leukosis virus-induced erythroblastosis: clustered integration sites and the arrangement of provirus in the c-erbB alleles.

There is considerable evidence that links the activation of cellular genes to oncogenesis. We previously reported that structural rearrangements in the cellular oncogene c-erbB correlate with the development of erythroblastosis induced by avian leukosis virus (ALV). c-erbB recently has been shown to be related to the gene encoding epidermal growth factor receptor. We now have characterized the detailed mechanisms of c-erbB activation by ALV proviruses. We report here that the ALV proviral integration sites are clustered 5' to the region where homology to v-erbB starts, suggesting that interruption in this region of c-erbB is important for its activation. The proviruses are oriented in the same transcriptional direction as c-erbB and usually are full-size. The latter finding is in contrast to the frequent deletions observed within the c-myc-linked proviruses in B-cell lymphomas. We have also identified a second c-erbB allele, which differs from the previously known allele primarily by a deletion in an intron region. This allele is also oncogenic upon mutation by an ALV provirus.

Alleles↗

PubMed1989

The v-sea oncogene of avian erythroblastosis retrovirus S13: another member of the protein-tyrosine kinase gene family.

The cloning and sequencing of the oncogene of the avian erythroblastosis virus S13 is described. The oncogene, termed v-sea, was found to be another member of the protein-tyrosine kinase gene family. The oncogene was fused in frame with the retrovirus S13 envelope gene, thus generating a fusion protein with a structure resembling that of a growth factor receptor. Sequence comparisons revealed that the v-sea gene was most closely related to the insulin receptor family of protein-tyrosine kinases, the greatest similarity being with the human MET oncogene.

Alpharetrovirus↗

PubMed1975

Hemolytic anemia induced by murine erythroblastosis virus: possible mechanisms of hemolysis and effects of an interferon inducer.

Murine erythroblastosis virus (MuEV), also called murine leukemia virus-Kirsten, is a member of the murine type-C-RNA leukemia-sarcoma group of oncogenic viruses. Like other members of this group, MuEV can elicit both a hemolytic disorder and an oncogenic response. Neonatal rats infected with MuEV succumb to this hemolytic disorder unless they are treated with the synthetic double-stranded polyribonucleotide, polyinosinic-polycytidylic acid (poly I-poly C). Animals receiving poly I-poly C had markedly reduced levels of virus reproduction as measured by bioassay and electron microscopy. The proliferation of erythroblasts after MuEV infection in animals not receiving poly I-poly C appeared to be an erythropoietin-dependent compensatory response to hemolysis. The hemolysis itself seemed to require virus reproduction in the cell types affected. Administration of poly I-poly C to MuEV-infected rats inhibited virus reproduction and thus may circumvent the hemolytic disease syndrome. The ultrastructure of the virus and of the virus reproduction was also studied.

Anemia, Hemolytic↗

PubMed1976

In vitro studies on the enhancement of Rauscher virus-induced erythroblastosis by complete Freund's adjuvant in BALB/c mice.

Inoculation of complete Freund's adjuvant (CFA) into BALB/c mice either before or after infection with Rauscher murine leukemia virus (MuLV-R) led to an acceleration of the disease as determined by spleen weight. Treatment with CFA also induced a higher number of spleen erythroblast foci and, in the bone marrow, erythropoietin-independent cells that produced erythroid colonies in vitro. CFA induced in the bone marrow not only an increase in myeloid progenitor cells that can produce colonies in agar, but an ever larger increase in the number of erythroid colony-forming cells. Virus-induced erythroblastosis was probably enhanced by CFA due to the production of many target cells. The more primitive burst-forming cell, which produced large colonies of erythroid cells after 10 days in culture, was also physiologically transformed in MuLV-R-infected mice; bursts could be formed by cells of such animals in the absence of erythropoietin.

Animals↗

PubMed1981

Modification of the methylation pattern in the vicinity of the chicken globin genes in avian erythroblastosis virus transformed cells.

Having previously found a reduced transcription of globin genes and an abortive processing of the already transcribed globin pre-mRNA in Avian Erythroblastosis Virus (AEV) transformed cells (1), we compared the genomic DNA of these cells with that of normal chicken erythroblasts, using 32-P-labelled cDNA probes specific for the beta, alpha A and alpha D globin sequences. Restriction endonuclease digestion, electrophoresis of digests in agarose gels, Southern blotting and hybridization were carried out. Our results show that the overall genome organization is not disturbed in the immediate neighbourhood of the adult globin genes; the observed restriction fragments are identical for both DNAs after EcoRI, HindIII, BamHI and XbaI digestion, using the beta, alpha A and alpha D globin cDNA probes. However, we observe specific modifications at some methylation sites in the beta, beta-like and alpha D regions: after HpaII or MspI digestion in the alpha D region and after HhaI digestion in the beta and beta-like region, heavier bands appear in the transformed cell DNA in addition to the ones observed in normal DNA. This implies that, at some specific sites, the transformed cell DNA is more methylated than the normal erythroblast DNA. The possible significance of this observation is discussed.

Alpharetrovirus↗

PubMed1983

Virus gene expression in rat cells transformed by avian myelocytomatosis virus strain MC29 and avian erythroblastosis virus.

Virus gene expression in rat cells transformed by either avian myelocytomatosis virus strain MC29 or avian erythroblastosis virus has been studied by biological and biochemical methods. In the clones examined, virus-specific sequences were found to be transcribed into RNA and, in most clones, the characteristic gag-related proteins could be identified. The transformed rat cells were fused to permissive chick cells and the rescued virus was shown to transform both chick embryo fibroblasts and the appropriate haemopoietic cell type in chick bone marrow cultures. These results clearly demonstrate that, as with the non-defective avian sarcoma viruses, the genetic information responsible for transformation by the defective avian leukaemia viruses can be expressed in non-permissive mammalian host cells as well as in permissive avian cells.

Alpharetrovirus↗

PubMed1985

Unclassified type of congenital dyserythropoietic anaemia (CDA) with prominent peripheral erythroblastosis.

Two unrelated cases of congenital dyserythropoietic anaemia (CDA) are described. They show striking similarities which could not be attributed to one of the well-known types of CDA or any other congenital disease of the erythroid system. Both patients were followed for many years before and after splenectomy. There was a long-lasting, prominent post-splenectomy erythroblastosis, suggesting impairment of red cell denucleation. The type of heredity is unknown, and the enzymatic or molecular basis of the changes observed is not understood.

Adult↗

PubMed1980

Cell-free translation of avian erythroblastosis virus RNA.

Avian erythroblastosis virus (AEV) RNA rescued from nonproducer cells by superinfection with a helper virus is translated into three polypeptides in the messenger-dependent rabbit reticulocyte lysate. A 75,000 molecular weight polypeptide (P75AEV) is synthesized from 28S RNA and is encoded by the 5' section of the AEV RNA, including gag-related and AEV-specific sequences. The P75AEV synthesized in infected cells and the P75AEV synthesized in the cell-free system are electrophoretically identical. A 44,000 molecular weight polypeptide (P44AEV) is synthesized from 20-24S RNA, apparently from the 3' section of the AEV-specific RNA sequence. A minor 37,000 molecular weight polypeptide (P37AEV) is synthesized from 20S AEV RNA. A comparison is drawn between the cell-free products of MC29 and AEV RNAs.

Alpharetrovirus↗

PubMed1986

Mutagenesis of the avian erythroblastosis virus erbB coding region: an intact extracellular domain is not required for oncogenic transformation.

Avian erythroblastosis virus (AEV) is an oncogenic retrovirus of birds. The AEV-encoded erbB polypeptide, a transmembrane glycoprotein bearing an N-terminal domain exposed on the surface of virally transformed cells, plays a crucial role in AEV-mediated oncogenesis. We report here a characterization of a mutated form of the AEV erbB protein which lacks over two-thirds of the extracellular region of this oncogenic protein. This mutant v-erbB protein, although lacking the three possible extracellular sites of N-linked protein glycosylation, appears unimpaired in the ability to transform cells to an oncogenic phenotype.

Alpharetrovirus↗

PubMed1988

Mutation of a protein kinase C phosphorylation site in the erbB protein of avian erythroblastosis virus.

Tumor promoter-stimulated phosphorylation of threonine 98 of the erbB protein of avian erythroblastosis virus (AEV) correlates with inhibition of erbB-dependent mitogenesis. To more clearly define the role of phosphorylation of this residue in regulation of the activity of the erbB protein, we have constructed erbB mutations which encode alanine (Ala-98), tyrosine (Tyr-98), or serine (Ser-98) at position 98. The biosynthesis and stability of the three mutant proteins were similar to those of the wild-type erbB protein, and all three retained the ability to transform chicken embryo fibroblasts. Treatment of transformed CEF with 12-tetradecanoylphorbol-13-acetate (TPA) stimulated incorporation of 32Pi into wild-type and mutant erbB proteins and resulted in a slight decrease in the electrophoretic mobilities of all the erbB proteins. Tryptic maps of erbB phosphopeptides showed no endogenous or TPA-stimulated phosphorylation of alanine 98 or tyrosine 98 in cells transformed by the Ala-98 and Tyr-98 mutants. Analysis of tryptic phosphopeptides by high-pressure liquid chromatography revealed that TPA treatment of cells stimulated phosphorylation of other sites of the erbB protein in addition to threonine 98. A high endogenous level of phosphorylation of serine 98 of the Ser-98 mutant protein was found, and TPA treatment of cells did not result in further phosphorylation of this residue. Cells transformed by wild-type and mutant AEV were equally sensitive to TPA-dependent inhibition of growth in soft agar and TPA-dependent inhibition of [3H]thymidine incorporation. TPA treatment inhibited tyrosine phosphorylation to a similar extent in cells transformed by wild-type or Ala-98 AEV. These data indicate that phosphorylation of threonine 98 of the erbB protein is not responsible for TPA-dependent inhibition of growth of AEV-transformed cells or TPA-induced inhibition of erbB-dependent tyrosine phosphorylation. TPA-stimulated phosphorylation of the erbB protein at other sites may mediate these effects. The data also show that subtle changes in a phosphorylation site (i.e., changing threonine to serine) can drastically alter recognition by protein kinases.

Alpharetrovirus↗

PubMed1988

The avian erythroblastosis virus erbA oncogene encodes a DNA-binding protein exhibiting distinct nuclear and cytoplasmic subcellular localizations.

The protein product of the v-erbA oncogene of avian erythroblastosis virus was analyzed by use of site-specific antisera. The v-erbA protein was found to exist in distinct nuclear and cytoplasmic forms. Both nuclear and cytoplasmic species of the v-erbA protein were capable of binding to DNA, a property predicted based on the structural relatedness the v-erbA polypeptide shares with the thyroid and steroid hormone receptors. A mutation within the v-erbA coding region which inhibited DNA binding and nuclear localization also inhibited the ability of the v-erbA protein to potentiate erythroid transformation, consistent with a model of the v-erbA protein as a transcriptional regulator.

Alpharetrovirus↗

PubMed1989

The ets sequence is required for induction of erythroblastosis in chickens by avian retrovirus E26.

E26 is a replication-defective avian retrovirus that causes an erythroblastic leukemia in vivo and transforms hematopoietic precursor cells of both the erythroid and the myeloid lineages in vitro. The E26 genome contains two sets of cell-derived sequences, ets and myb. myb sequences are also present in avian myeloblastosis virus, which transforms myeloblasts exclusively. To determine whether the ets sequence is responsible for the erythroid specificity of E26, we analyzed the transforming activities of several viruses carrying mutations in the ets sequence constructed in vitro. The mutant viruses retained the ability to transform myeloid cells in vitro, indicating that the myb oncogene is sufficient for this viral function. However, the ets-deficient viruses did not cause an overt leukemia in chickens. The results indicate that the ets sequence is required for the induction of erythroblastosis by E26.

Alpharetrovirus↗