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PubMed2002

Concomitant activation of the PI3K-Akt and the Ras-ERK signaling pathways is essential for transformation by the V-SEA tyrosine kinase oncogene.

V-SEA is the transforming component of S13 Avian Erythroblastosis Retrovirus that causes erythroblastosis and anemia in chicken. Like all members in the family (MET, RON, SEA), its cytosolic domain possesses two tyrosine autophosphorylation sites in the tandemly arranged bidentate motif that serve as docking sites for SH2 domain-containing proteins. Here, we investigated phosphotyrosine-dependent activation of signaling pathways and their significance in V-SEA-induced transformation and/or proliferation. We demonstrated that V-SEA activates the PI3K-Akt signaling pathway primarily in Y557- and secondarily in Y564-dependent manner. V-SEA was also shown to induce the tyrosine phosphorylation of the Gab2 protein, leading to PI3K association and thus providing an alternative route for PI3K activation. On the other hand, activation of the Ras-ERK pathway is primarily via Y564 and secondarily via Y557. A dominant-negative form of Ras inhibited V-SEA-induced ERK phosphorylation in concentration dependent manner suggesting the importance of the Grb2-Ras signaling axis in V-SEA-induced ERK activation. The biological significance of activation of the PI3K-Akt and the Ras-ERK pathways in V-SEA-induced transformation was analysed in the V-SEA-RAT1 and V-SEA-3T3 cell lines by employing specific inhibitors, LY294002 and PD98059 compounds. Both the PD and LY compounds inhibited cell growth, but only the PD compound caused reversion of the transformed phenotype. In addition, both compounds inhibited focal colony formation by the transformants in soft agar. Thus, transformation by the V-SEA oncogene is a function of the concomitant activation of, at least, the PI3K-Akt and Ras-ERK signaling pathways that regulate cell growth and morphology.

Adaptor Proteins, Signal Transducing↗

PubMedDate not supplied

[Mechanism of virus-induced leukemogenesis in an animal model system].

Retroviruses can cause different types of leukemias in chickens. A small group of virus strains induce acute leukemias and transform hematopoietic cells in vitro. We have shown that cells transformed in vitro by erythroblastosis and myeloblastosis viruses resemble in vivo transformed cells in their phenotype of differentiation. The erythroblastosis virus AEV carries two cell-derived oncogenes termed erbA and erbB. The analysis of AEV using deletion mutants showed that erbB is the main oncogene which is capable of inducing a "mild" form of erythroleukemia. The added action of the erbA oncogene leads to an aggressive, more "advanced" form of erythroleukemia. The erbA oncogene itself, however, does not exhibit any detectable biological activity. Using temperature sensitive mutants of AEF we could also show that erbB, together with erbA, blocks the differentiation of hematopoietic precursor cells. The continued synthesis of a functional erbB-encoded protein is necessary to maintain the "blocked", i.e. leukemic state of the infected cells.

Alpharetrovirus↗

PubMed1987

[Incidence of parvovirus B19 infection. Seroepidemiologic studies].

Anti-B19-IgG antibodies were tested for by the ELISA method in 768 sera, 76 from children and juveniles, aged 1-15 years, attending the Outpatients Department of the Children's Clinic, University of Munich, and 692 from persons, aged 18-68 years, attending the blood donor service of the Bavarian Red Cross in Munich. 38.4% of sera were positive, with a significant difference between men and women (32.5% vs. 47.5%, P less than or equal to 0.01). A fresh B19 infection was present in 42 subjects by demonstrating anti-B19-IgM in the ELISA test. The sera came from seven patients with infectious erythema, 26 with skin rash of uncertain cause, two with erythroblastosis fetalis, two with enteritis, one with transitory anaemia, one with juvenile polyarthritis, one with lymphadenitis and arthralgia, and two with an asymptomatic course. Viral B19-DNA was demonstrated by nucleic acid hybridization in a blood unit from an asymptomatic blood donor and in amniotic fluid in a case of erythroblastosis fetalis.

Adolescent↗

PubMed1980

Fujinami sarcoma virus: an avian RNA tumor virus with a unique transforming gene.

The oncogenic properties and RNA of the Fujinami avian sarcoma virus (FSV) and the protein it encodes were investigated and compared to those of other avian tumor viruses with sarcomagenic properties such as Rous sarcoma virus and the acute leukemia viruses MC29 and erythroblastosis virus. Cloned stocks of FSV caused sarcomas in all chickens inoculated and were found to contain a 4.5-kilobase (kb) and an 8.5-kb RNA species. The 4.5-kb RNA was identified as the genome of defective FSV because it was absent from nondefective FSV-associated helper virus and because the titer of focus-forming units increased with the ratio of 4.5-kb to 8.5-kb RNA in virus preparations. This is, then, the smallest known tumor virus RNA with a transforming function. Comparisons with other viral RNAs, based on oligonucleotide mapping and molecular hybridization, indicated that 4.5-kb FSV RNA contains a 5' gag gene-related sequence of 1 kb, an internal specific sequence of about 3 kb that is unrelated to Rous sarcoma virus, MC29, and erythroblastosis virus, and a 3'-terminal sequence of about 0.5 kb related to the conserved C region of avian tumor viruses. The lack of some or all nucleotide sequences of the essential virion genes, gag, pol, and env, and the isolation of FSV-transformed nonproducer cell clones indicated that FSV is replication defective. A 140,000-dalton, gag-related non-structural protein was found in FSV-transformed producer and nonproducer cells and was translated in vitro from full-length FSV RNA. This protein is expected to have a transforming function both because its intracellular concentration showed a positive correlation with the percentage of transformed cells in a culture and because FSV is unlikely to code for major additional proteins since the genetic complexities of FSV RNA and the FSV protein are almost the same. It is concluded that the transforming onc gene of FSV is distinct from that of Rous sarcoma virus and other avian tumor viruses with sarcomagenic properties. Hence, multiple mechanisms exist for sarcomagenic transformation of avian cells.

Alpharetrovirus↗

PubMed1997

Cell surface organization of the erythropoietin receptor complex differs depending on its mode of activation.

During erythroid development erythropoietin (EPO) binds specifically to a receptor primarily present on committed erythroid progenitors, stimulating mitogenic, survival, and differentiative growth response pathways. Other modes of erythropoietin receptor (EPO-R) activation, such as interaction with the env gene Friend virus envelope glycoprotein (F-gp55) of spleen focus-forming virus or specific mutations in the extracellular domain of the EPO-R, give rise to pathological consequences, in vivo and EPO-independent proliferation and differentiation of cultured cells. Activating extracellular receptor mutations result in covalently linked receptor homodimers. These observations and others have led to the proposal that EPO activates the EPO-R by inducing dimer formation on the cell surface. It has been assumed that F-gp55 also induces dimer formation of the EPO-R; however, clear evidence of this is lacking. In addition, EPO and F-gp55 stimulation of the EPO-R elicit different biological responses. To probe whether the cell surface EPO-R is structurally different with these activators, we contrasted the cell surface EPO-R complex formed following receptor activation by EPO, F-gp55, and mutations in the extracellular domain of the receptor. Our results indicate that cell surface forms of activated EPO-R differ, as judged by their differential association with F-gp55 and pattern of associated cell surface proteins. Interestingly, we find that the env gene of an anemic strain of Friend virus, Rauscher virus envelope glycoprotein, does not interact with the EPO-R at the cell surface. Thus, the mode of Rauscher virus envelope glycoprotein-induced erythroblastosis may be distinct from F-gp55-induced erythroblastosis and possibly not involve the EPO-R.

Animals↗

PubMed2004

Nuclear export of the oncoprotein v-ErbA is mediated by acquisition of a viral nuclear export sequence.

v-ErbA, an oncogenic derivative of the thyroid hormone receptor alpha (TRalpha) carried by the avian erythroblastosis virus, contains several alterations including fusion of a portion of avian erythroblastosis virus Gag to its N terminus, N- and C-terminal deletions, and 13 amino acid substitutions. Nuclear export of v-ErbA occurs through a CRM1-mediated pathway. In contrast, nuclear export of TRalpha and another isoform, TRbeta, is CRM1-independent. To determine which amino acid changes in v-ErbA confer CRM1-dependent nuclear export, we expressed a panel of green and yellow fluorescent protein-tagged mutant and chimeric proteins in mammalian cells. The sensitivity of subcellular trafficking of these mutants to leptomycin B (LMB), a specific inhibitor of CRM1, was assessed by fluorescence microscopy. Our data showed that a nuclear export sequence resides within a 70-amino acid domain in the C-terminal portion of the p10 region of Gag, and in vitro binding assays demonstrated that Gag interacts directly with CRM1. However, a panel of ligand-binding domain mutants of v-ErbA lacking the Gag sequence exhibited greater nuclear localization in the presence of LMB, suggesting that the various amino acid substitutions/deletions may cause a conformation shift, unmasking an additional CRM1-dependent nuclear export sequence. In contrast, the altered DNA-binding domain of the oncoprotein did not contribute to CRM1-dependent nuclear export. Heterokaryon experiments revealed that v-ErbA did not undergo nucleocytoplasmic shuttling when the CRM1 export pathway was blocked by LMB treatment, suggesting that the ability to follow the export pathway used by TRalpha has been lost by the oncoprotein during its evolution. Our findings thus point to the intriguing possibility that acquisition of altered nuclear export capabilities contributes to the oncogenic properties of v-ErbA.

Active Transport, Cell Nucleus↗

PubMed2001

Lethal hydrops fetalis due to congenital dyserythropoietic anemia in a newborn: association of a new skeletal abnormality.

Congenital dyserythropoietic anemias (CDAs) are a group of hereditary refractory anemias characterized by ineffective erythropoiesis, typical morphological abnormalities of erythroblasts, a low or no reticulocyte response, hyperbilirubinemia, and splenomegaly. A massive hydropic newborn born with a very severe anemia (Hb 4.8 g/dL), diffuse edema, hepatosplenomegaly, ascites, pulmonary edema and respiratory distress, and shortness and hallux varus deformity of the great toe of the right foot was diagnosed to have congenital dyserythropoietic anemia on the basis of the hematological (macrocytosis, anisopoikilocytosis, fragmented red cells and erythroblastosis in the peripheral blood, and erythroid hyperplasia with erythroblastosis and erythroblasts with double nuclei and thin chromatin bridges connecting these nuclei in the bone marrow) and serological (negative acidified serum lysis test and no agglutination with anti-i antibodies) findings. In this article the seventh case of neonatal congenital dyserythropoietic anemia presenting with a very severe (lethal) form of hydrops fetalis and a new (hallux varus) deformity of the great toe of the right foot is presented. Congenital dyserythropoietic anemia should be considered in the differential diagnosis of hydrops fetalis presenting with a very severe anemia and a skeletal abnormality of the great toe.

Anemia, Dyserythropoietic, Congenital↗

PubMed2004

Fetal and embryonic hemoglobins in erythroblasts from fetal blood and fetal cells enriched from maternal blood in pregnancies complicated by maternal diabetes mellitus.

OBJECTIVES: To determine whether there is a delay or reversal in switch mechanisms from embryonic (epsilon and zeta) to fetal (gamma) hemoglobins accompanying the erythroblastosis in fetuses of diabetic mothers, and whether the increased erythroblast count in the fetal blood is associated with an increase in fetomaternal cell trafficking. MATERIALS AND METHODS: Fetal and maternal blood samples were obtained from 11 fetuses and five pregnant women in pregnancies complicated by maternal diabetes mellitus. Blood samples were also taken as controls from 35 fetuses and 33 mothers. Fetal erythroblasts were isolated by triple density gradient centrifugation and magnetic cell sorting with anti-CD71 antibody. Fluorescent antibodies were used to immunostain for gamma (gamma), epsilon (epsilon) and zeta (zeta) hemoglobin chains. In the maternal samples, fluorescence in situ hybridization for X and Y chromosomes was also carried out, to confirm the presence and proportion of enriched fetal cells from the maternal blood. RESULTS: In both fetal and maternal blood the median percentages of erythroblasts positive for gamma-globin, epsilon-globin and zeta-globin chains were significantly higher in fetuses of diabetic mothers compared to controls (fetus, gamma-globin, 76 vs. 64%, p < 0.0001; epsilon-globin, 4 vs. 0%, p < 0.0001; zeta-globin, 4 vs. 0%; p < 0.0001; mother, gamma-globin, 14 vs. 1%, p < 0.0005; epsilon-globin, 0.25 vs. 0%, p < 0.0003; zeta-globin, 0.2 vs. 0%, p < 0.0003). The median percentage of cells with Y signals in maternal blood was also higher in diabetic pregnancies compared to normal controls (7.5 vs. 1%, p < 0.002). CONCLUSIONS: The findings suggest that the fetal erythroblastosis in diabetic pregnancies is accompanied by a delay in the switch from embryonic to fetal hemoglobin chains. In addition, it is associated with an increase in fetomaternal cell trafficking.

Case-Control Studies↗

PubMed1975

Phosphoproteins: structural components of oncornaviruses.

Oncornaviruses, which contain a virion-associated protein kinase, were found to possess phosphoproteins as virion structural components. One major phosphoprotein common to strains of laboratory and wild mouse oncornaviruses and a strain of feline leukemia virus was shown to be a polypeptide of about 12, 000 mol wt. In addition to this, the Kirsten strain of murine sarcoma virus contained a second major phosphoprotein of about 10, 000 mol wt, and mouse erythroblastosis virus contained a second major phosphoprotein that was either identical to or comigrated with the virion glycoprotein of about 74, 000 mol wt. The major phosphoprotein of RD-114 virus was found to be of about 16, 000 mol wt. The major phosphoamino acid of the 12, 000-mol wt polypeptide of the mouse erythroblastosis virus was identified as phosphoserine, and that of the 16, 000-mol wt polypeptide of the RD-114 virus was identified as phosphothreonine.

Electrophoresis, Paper↗

PubMed1985

Induction of angiosarcoma by a c-erbB transducing virus.

Recently, 12 new transductions of c-erbB have been identified in a series of Rous-associated virus type 1-induced erythroleukemias. During the passage of these new transducing viruses it has become apparent that the erythroleukemia in chicken 5005 contained two different c-erbB transducing viruses. One induces erythroblastosis, whereas the second induces angiosarcoma. The angiosarcoma- and erythroblastosis-inducing viruses appear to have had a common ancestor, since tumors induced by each contain a novel, 4.3-kilobase c-erbB-related EcoRI fragment. The angiosarcoma-inducing virus has been named avian angiosarcoma virus and is designated for the chicken in which it originated.

Animals↗

PubMed1986

Rous-associated virus 1-induced erythroleukemic cells exhibit a weakly transformed phenotype in vitro and release c-erbB-containing retroviruses unable to transform fibroblasts.

Avian leukosis viruses induce erythroblastosis in chicks by integrating into the c-erbB gene and thus activating c-erbB transcription. We characterized Rous-associated virus 1-induced leukemic erythroblasts in vitro and showed that they mostly resemble erythropoietin-independent but otherwise normal erythroid progenitors. Some leukemic cells, however, were able to both differentiate and proliferate extensively in vitro. All 14 leukemias studied expressed high levels of erbB-related proteins that were 5 to 10 kilodaltons larger but otherwise very similar to the gp74erbB protein of avian erythroblastosis virus ES4 with respect to biosynthesis, glycosylation, and cell surface expression. Two leukemias contained and released retroviruses that transduced erbB. Chicken embryo fibroblasts fully infected with these viruses expressed high levels of erbB RNA and protein but retained a normal phenotype. Our results suggest that certain forms of c-erbB, activated by long terminal repeat insertion or viral transduction, are capable of inducing erythroleukemia but unable to transform fibroblasts.

Animals↗

PubMed1990

Ectopic expression of the erythrocyte band 3 anion exchange protein, using a new avian retrovirus vector.

A retrovirus vector was constructed from the genome of avian erythroblastosis virus ES4. The v-erbA sequences of avian erythroblastosis virus were replaced by those coding for neomycin phosphotransferase, creating a gag-neo fusion protein which provides G418 resistance as a selectable marker. The v-erbB sequences following the splice acceptor were replaced by a cloning linker allowing insertion of foreign genes. The vector has been tested in conjunction with several helper viruses for the transmission of G418 resistance, titer, stability, transcription, and the transduction and expression of foreign genes in both chicken embryo fibroblasts and the QT6 quail cell line. The results show that the vector is capable of producing high titers of Neor virus from stably integrated proviruses. These proviruses express a balanced ratio of genome length to spliced transcripts which are efficiently translated into protein. Using the Escherichia coli beta-galactosidase gene cloned into the vector as a test construct, expression of enzyme activity could be detected in 90 to 95% of transfected target cells and in 80 to 85% of subsequently infected cells. In addition, a cDNA encoding the avian erythrocyte band 3 anion exchange protein has been expressed from the vector in both chicken embryo fibroblasts and QT6 cells and appears to function as an active, plasma membrane-based anion transporter. The ectopic expression of band 3 protein provides a visual marker for vector function in these cells.

Alpharetrovirus↗

PubMed1993

Induction of renal adenocarcinoma by a nonmutated erbB oncogene.

Oncogenicity tests have revealed that a nonmutated erbB oncogene induces renal adenocarcinoma in addition to erythroblastosis. The erbB oncogene is a truncated form of the chicken epidermal growth factor receptor that lacks the extracellular ligand-binding domain. Previously, the nonmutated erbB oncogene has been reported to cause only erythroblastosis. The expansion of the disease potential of erbB to additional neoplasms has been associated with mutations (truncations, deletions, and point mutations) within the erbB gene. Our results indicate that a nonmutated virally expressed erbB oncogene (REB-c) causes a 100% incidence of renal neoplasia.

Adenocarcinoma↗

PubMed1998

An array of novel murine spleen focus-forming viruses that activate the erythropoietin receptor.

The Friend spleen focus-forming virus (SFFV) env gene encodes a 409-amino-acid glycoprotein with an apparent Mr of 55,000 (gp55) that binds to erythropoietin receptors (EpoR) to stimulate erythroblastosis. We reported previously the in vivo selection during serial passages in mice of several evolutionary intermediates that culminated in the formation of a novel SFFV (M. E. Hoatlin, E. Gomez-Lucia, F. Lilly, J. H. Beckstead, and D. Kabat, J. Virol. 72:3602-3609, 1998). A mouse injected with a retroviral vector in the presence of a nonpathogenic helper virus developed long-latency erythroblastosis, and subsequent viral passages resulted in more pathogenic isolates. The viruses taken from these mice converted an erythropoietin-dependent cell line (BaF3/EpoR) into factor-independent derivatives. Western blot analysis of cell extracts with an antiserum that broadly reacts with murine retroviral envelope glycoproteins suggested that the spleen from the initial mouse with mild erythoblastosis contained an array of viral components that were capable of activating EpoR. DNA sequence analysis of the viral genomes cloned from different factor-independent cell clones revealed env genes with open reading frames encoding 644, 449, and 187 amino acids. All three env genes contained 3' regions identical to that of SFFV, including a 6-bp duplication and a single-base insertion that have been shown previously to be critical for pathogenesis. However, the three env gene sequences did not contain any polytropic sequences and were divergent in their 5' regions, suggesting that they had originated by recombination and partial deletions of endogenously inherited MuLV env sequences. These results suggest that the requirements for EpoR activation by SFFV-related viruses are dependent on sequences at the 3' end of the env gene and not on the polytropic regions or on the 585-base deletions that are common among the classical strains of SFFV. Moreover, sequence analysis of the different recombinants and deletion mutants revealed that short direct and indirect repeat sequences frequently flanked the deletions that had occurred, suggesting a reverse transcriptase template jumping mechanism for this rapid retroviral diversification.

Amino Acid Sequence↗

PubMed1984

Cellular oncogenes (c-erb-A and c-erb-B) located on different chicken chromosomes can be transduced into the same retroviral genome.

Avian erythroblastosis virus has transduced two cellular genes, c-erb-A and c-erb-B. Using fractionated chicken chromosomes, we found that the two genes are located on different chromosomes in the chicken genome: c-erb-A is on a microchromosome, and c-erb-B is on a large chromosome. The locations of two other cellular oncogenes (c-fps and c-myb) were also determined: c-fps is on a microchromosome, and c-myb is on chromosome of an intermediate size. Our results suggest that avian erythroblastosis virus had transduced the two cellular genes independently, conforming to previous indications that cellular oncogenes are dispersed among multiple chromosomes in every species that has been examined.

Alpharetrovirus↗

PubMed1994

Umbilical cord blood erythroblast count as an index of intrauterine hypoxia.

The relation of umbilical cord blood arterial pH, Apgar score, leucocyte count, and erythroblast count at delivery with the diagnosis of fetal distress in labour was studied prospectively in three groups of singleton pregnancies delivering at term vaginally (55 infants), by elective caesarean section (39 infants), or by emergency caesarean section for abnormal intrapartum fetal heart rate patterns (55 infants). In the emergency caesarean section group the umbilical cord blood arterial pH was significantly lower and the leucocyte and erythroblast counts were higher than in the elective caesarean section group. Comparison of the emergency caesarean section and spontaneous vaginal delivery groups showed significant differences for pH and erythroblast count, but not for leucocyte count. In the spontaneous vaginal delivery group erythroblastosis was associated with umbilical cord blood pH, whereas leucocytosis was associated with the length of labour. The five minute Apgar score was > or = 7 in all infants. This study suggests that leucocytosis is a non-specific response of the fetus to labour, whereas erythroblastosis reflects fetal tissue hypoxia.

Erythroblasts↗

PubMed1988

Assessment of fetal blood volume for computer-assisted management of in utero transfusion.

We performed 41 intravascular ultrasound-guided fetal transfusions in a total of 20 pregnancies with erythroblastosis fetalis or alloimmune thrombocytopenia. On the basis of this experience, we developed a computer-assisted procedure for determining the volume to be transfused, which provides an adequate final concentration. Fetal weight was estimated using ultrasound measurements. Fetoplacental blood volume was estimated from the regression line: fetoplacental volume (ml) = 1.046 + fetal weight (g) X 0.14. The volume to be transfused was calculated using the simple dilution formula: Vtransfused = Vfetoplacental.(Cfinal - Cinitial)/Ctransfused where C is the hematocrit or platelet count. The entire procedure is computerized, simple and rapid, and avoids resorting to repeated intermediate sampling. The dilution formula used appears to be more reliable than a formula taking into account the volume added, even in erythroblastosis fetalis where relatively large volumes are injected. This suggests rapid plasma loss during the procedure.

Blood Physiological Phenomena↗

PubMed1978

Amniotic fluid reverse triiodothyronine in complicated pregnancy.

The concentrations of reverse triiodothyronine (3,3',5'-T3 or rT3) in amniotic fluid (AF) were measured by radioimmunoassay in 81 patients with various complications of pregnancy and in 39 normal pregnant patients at equivalent gestational age. In normal pregnancy, AFrT3 concentrations decreased with advancing gestational age. At 21-25, 26-30, 31-35, and 36-40 weeks of normal pregnancy, AFrT3 concentrations (mean +/- SE) were 353 +/- 62 (n = 6), 131 +/- 49 (n = 7), 94 +/- 25 (n = 14), and 93 +/- 5 (n = 20) ng/dl, respectively (ranges: 200-600, 57-350, 66-135, and 50-135). Both normal and supranormal values of AFrT3 were found in patients with complicated pregnancy. In patients with RH isoimmune disease, higher than normal AFrT3 concentrations were associated with seriously affected or gravely ill fetuses wheras normal AFrT3 concentrations predicted a more favorable outcome. There was a good correlation between AFrT3 and AF pigment (deltaOD450) levels (r = 0.70, P less than 0.001). In complicated pregnancy other than erythroblastosis fetalis, AFrT3 concentrations were not of any prognostic significance, and there was no correlation between AFrT3 and lecithin/spingomyelin ratio. The data suggest that AFrT3 determination may help in the assessment of the fetal condition in erythroblastosis fetalis.

Amniotic Fluid↗