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PubMedDate not supplied

Chromosomal localization of the human proto-oncogene c-ets.

E26 is an acute leukaemia avian retrovirus which induces myeloblastosis and erythroblastosis in vivo and transforms erythroblasts and myeloblasts in vitro. It contains the oncogene v-myb (ref. 4), first described for avian myeloblastosis virus (AMV), as well as a second specific nucleotide sequence, v-ets located 3' to v-myb (refs 5,6). We have reported that v-ets has a cellular counterpart (c-ets) in chicken and human DNA. Now, using two independent methods--hybridization with human c-ets probe of sorted chromosomes and in situ hybridization--we report the localization of the ets locus on human chromosome 11 at bands q23-q24. This finding may be important, as specific breakpoints around this position have been reported for human malignancies such as acute monocytic leukaemia and Ewing's sarcoma.

Base Sequence↗
PubMedDate not supplied

Autophosphorylation sites on the epidermal growth factor receptor.

The epidermal growth factor (EGF) receptor is a tyrosine-specific protein kinase with autophosphorylating activity. A 300 amino acid-long region of the receptor's cytoplasmic domain matches (35-90% homology) sequences of transforming proteins from the src family and includes a putative nucleotide binding site. Several of the src transforming proteins have tyrosine kinase activity, but v-erb-B, which appears to be a truncated EGF receptor, is virtually identical to the receptor over this region and yet lacks detectable kinase activity. To locate possible acceptor sites in the v-erb-B protein, we have mapped these sites in the human EGF receptor. We report here that three tyrosine sites near the C-terminus are phosphorylated in vitro. In intact cells, we find that EGF stimulates phosphorylation of several sites, the tyrosine 14 residues from the C-terminus being modified the most extensively. The equivalent site is absent in the v-erb-B protein of avian erythroblastosis virus (AEV) and may influence tyrosine kinase activity.

Amino Acid Sequence↗
PubMedDate not supplied

Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin.

Epidermal growth factor (EGF), through interaction with specific cell surface receptors, generates a pleiotropic response that, by a poorly defined mechanism, can induce proliferation of target cells. Subversion of the EGF mitogenic signal through expression of a truncated receptor may be involved in transformation by the avian erythroblastosis virus (AEV) oncogene v-erb-B, suggesting that similar EGF receptor defects may be found in human neoplasias. Overexpression of EGF receptors has been reported on the epidermoid carcinoma cell line A431, in various primary brain tumours and in squamous carcinomas. In A431 cells the receptor gene is amplified. Here we show that 4 of 10 primary brain tumours of glial origin which express levels of EGF receptors that are higher than normal also have amplified EGF receptor genes. Amplified receptor genes were not detected in the other brain tumours examined. Further analysis of EGF receptor defects may show that such altered expression and amplification is a particular feature of certain human tumours.

Brain Neoplasms↗
PubMedDate not supplied

Domain structure of human glucocorticoid receptor and its relationship to the v-erb-A oncogene product.

The interaction of steroids with their nuclear receptors induces a cascade of regulatory events that results from the activation of specific sets of genes by the hormone/receptor complex. Steroids, either acting alone or possibly synergistically with other growth factors, can influence the DNA synthesis and proliferation of specific target cells, initiate developmental pathways and activate expression of the differentiated phenotype. Moreover, steroid hormones have been implicated in abnormal growth regulation both in tumours and tumour-derived cell lines. The identification of complementary DNAs encoding the human glucocorticoid receptor (hGR) predicts two protein forms (alpha and beta; 777 and 742 amino acids long, respectively) which differ at their carboxy termini. We report here that both forms of the receptor are related, with respect to their domain structure, to the v-erb-A oncogene product of avian erythroblastosis virus (AEV), which suggests that steroid receptor genes and the c-erb-A proto-oncogene are derived from a common primordial regulatory gene. Therefore, oncogenicity by AEV may result, in part, from the inappropriate activity of a truncated steroid receptor or a related regulatory molecule encoded by v-erb-A. This suggests a mechanism by which transacting factors may facilitate transformation. We also identify a short region of hGR that is homologous with the Drosophila homoeotic proteins encoded by Antennapedia and fushi tarazu.

Alpharetrovirus↗
PubMedDate not supplied

Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A.

We have cloned and sequenced the complete complementary DNA of the oestrogen receptor (ER) present in the breast cancer cell line MCF-7. The expression of the ER cDNA in HeLa cells produces a protein that has the same relative molecular mass and binds oestradiol with the same affinity as the MCF-7 ER. There is extensive homology between the ER and the erb-A protein of the oncogenic avian erythroblastosis virus.

Amino Acid Sequence↗
PubMed2006

Gene expression in blood changes rapidly in neutrophils and monocytes after ischemic stroke in humans: a microarray study.

Ischemic brain and peripheral white blood cells release cytokines, chemokines and other molecules that activate the peripheral white blood cells after stroke. To assess gene expression in these peripheral white blood cells, whole blood was examined using oligonucleotide microarrays in 15 patients at 2.4+/-0.5, 5 and 24 h after onset of ischemic stroke and compared with control blood samples. The 2.4-h blood samples were drawn before patients were treated either with tissue-type plasminogen activator (tPA) alone or with tPA plus Eptifibatide (the Combination approach to Lysis utilizing Eptifibatide And Recombinant tPA trial). Most genes induced in whole blood at 2 to 3 h were also induced at 5 and 24 h. Separate studies showed that the genes induced at 2 to 24 h after stroke were expressed mainly by polymorphonuclear leukocytes and to a lesser degree by monocytes. These genes included: matrix metalloproteinase 9; S100 calcium-binding proteins P, A12 and A9; coagulation factor V; arginase I; carbonic anhydrase IV; lymphocyte antigen 96 (cluster of differentiation (CD)96); monocarboxylic acid transporter (6); ets-2 (erythroblastosis virus E26 oncogene homolog 2); homeobox gene Hox 1.11; cytoskeleton-associated protein 4; N-formylpeptide receptor; ribonuclease-2; N-acetylneuraminate pyruvate lyase; BCL6; glycogen phosphorylase. The fold change of these genes varied from 1.6 to 6.8 and these 18 genes correctly classified 10/15 patients at 2.4 h, 13/15 patients at 5 h and 15/15 patients at 24 h after stroke. These data provide insights into the inflammatory responses after stroke in humans, and should be helpful in diagnosis, understanding etiology and pathogenesis, and guiding acute treatment and development of new treatments for stroke.

Adult↗
PubMed2001

The v-ErbA oncoprotein quenches the activity of an erythroid-specific enhancer.

v-ErbA is a mutated variant of thyroid hormone receptor (TRalpha/NR1A1) borne by the Avian Erythroblastosis virus causing erythroleukemia. TRalpha is known to activate transcription of specific genes in the presence of its cognate ligand, T3 hormone, while in its absence it represses it. v-ErbA is unable to bind ligand, and hence is thought to contribute to leukemogenesis by actively repressing erythroid-specific genes such as the carbonic anhydrase II gene (CA II). In the prevailing model, v-ErbA occludes liganded TR from binding to its cognate elements and constitutively interacts with the corepressors NCoR/SMRT. We previously identified a v-ErbA responsive element (VRE) within a DNase I hypersensitive region (HS2) located in the second intron of the CA II gene. We now show that HS2 fulfils all the requirements for a genuine enhancer that functions independent of its orientation and position with a profound erythroid-specific activity in normal erythroid progenitors (T2ECs) and in leukemic erythroid cell lines. We find that the HS2 enhancer activity is governed by two adjacent GATA-factor binding sites. v-ErbA as well as unliganded TR prevent HS2 activity by nullifying the positive function of factors bound to GATA-sites. However, v-ErbA, in contrast to TR, does not convey active repression to silence the transcriptional activity intrinsic to a heterologous tk promoter. We propose that depending on the sequence and context of the binding site, v-ErbA contributes to leukemogenesis by occluding liganded TR as well as unliganded TR thereby preventing activation or repression, respectively.

Animals↗
PubMed2001

Leukemic transformation of normal murine erythroid progenitors: v- and c-ErbB act through signaling pathways activated by the EpoR and c-Kit in stress erythropoiesis.

Primary erythroid progenitors can be expanded by the synergistic action of erythropoietin (Epo), stem cell factor (SCF) and glucocorticoids. While Epo is required for erythropoiesis in general, glucocorticoids and SCF mainly contribute to stress erythropoiesis in hypoxic mice. This ability of normal erythroid progenitors to undergo expansion under stress conditions is targeted by the avian erythroblastosis virus (AEV), harboring the oncogenes v-ErbB and v-ErbA. We investigated the signaling pathways required for progenitor expansion under stress conditions and in leukemic transformation. Immortal strains of erythroid progenitors, able to undergo normal, terminal differentiation under appropriate conditions, were established from fetal livers of p53-/- mice. Expression and activation of the EGF-receptor (HER-1/c-ErbB) or its mutated oncogenic version (v-ErbB) in these cells abrogated the requirement for Epo and SCF in expansion of these progenitors and blocked terminal differentiation. Upon inhibition of ErbB function, differentiation into erythrocytes occurred. Signal transducing molecules important for renewal induction, i.e. Stat5- and phosphoinositide 3-kinase (PI3K), are utilized by both EpoR/c-Kit and v/c-ErbB. However, while v-ErbB transformed cells and normal progenitors depended on PI3K signaling for renewal, c-ErbB also induces progenitor expansion by PI3K-independent mechanisms.

Animals↗
PubMed2005

Multiple mutations contribute to repression by the v-Erb A oncoprotein.

The v-Erb A oncoprotein of avian erythroblastosis virus is derived from c-Erb A, a hormone-activated transcription factor. Notably, v-Erb A has sustained multiple mutations relative to c-Erb A and functions as a constitutive transcriptional repressor. We report here an analysis of the contributions of these different mutations to v-Erb A function. Our experiments demonstrate that two amino-acid differences between v-Erb A and c-Erb A, located in the 'I-box,' alter the dimerization properties of the viral protein, resulting in more stable homodimer formation, increased corepressor binding, and increased target gene repression. An additional amino-acid difference between v- and c-Erb A, located in helix 3 of the hormone binding domain, renders corepressor binding by the viral protein more resistant to release by thyroid hormone. Finally, we report that a C-terminal truncation in v-Erb A not only inhibits exchange of corepressor and coactivator, as previously noted, but also permits v-Erb A to recruit both SMRT and N-CoR corepressors, whereas c-Erb A is selective for N-CoR. The latter two mutations in v-Erb A also impair its ability to suppress c-Jun function in response to T3 hormone. We propose that the acquisition of oncogenic potential by the v-Erb A protein was a multistep process involving a series of mutations that alter the transcriptional repressive properties of the viral protein through multiple mechanisms.

Animals↗
PubMed1985

Identification and characterization of the chicken transferrin receptor.

Among a panel of monoclonal antibodies that recognize chicken haematopoietic-differentiation antigens, one, JS 8, was found to immunoprecipitate a 95000-Mr cell-surface protein from chicken erythroblasts transformed with avian-erythroblastosis virus. This protein was shown, by affinity chromatography on immobilized chicken transferrin (conalbumin), to be the chicken transferrin receptor. Although immunologically unrelated to the human transferrin receptor, biochemical comparison of the chicken transferrin receptor to the human receptor showed similarities with respect to the pattern of biosynthesis, degree of glycosylation, dimerization in the absence of reducing agents and subcellular localization. The present report contrasts with recent ones describing the chicken transferrin receptor isolated from embryonic tissues as a 58000-Mr protein.

Animals↗
PubMed1997

An enhancer with cell-type dependent activity is located between the myeloid and epithelial aminopeptidase N (CD 13) promoters.

The 5' flanking region of the gene encoding the small intestinal brush-border peptidase aminopeptidase N (APN) was screened for the presence of enhancer regions. A 300 bp region with enhancer activity was identified 2.7 kb upstream of the transcriptional start site which is used in epithelial cells. The enhancer stimulated transcription from a heterologous promoter (the simian virus 40 early promoter) in a position- and orientation-independent manner. The activity of the enhancer is cell-type dependent and it is active in liver (HepG2), intestinal (Caco-2) and myeloid (K562) cells. As the epithelial APN promoter is active in the first two cell-types and the myeloid APN promoter in the last, the results may suggest that the enhancer, through a cooperation with either of the promoters, is important for the tissue-specific expression of APN. A detailed analysis of the enhancer led to the identification of four functionally important regions that are protected against DNase I digestion by Caco-2 nuclear extract. Sequence analysis suggests that two of the regions may interact with members of the Ets transcription factor family (Ets is a transformation-specific protein first discovered in the E26 avian erythroblastosis virus), one region with a CCAAT enhancer-binding protein and one region with Sp1, a transcriptional activator first described as a factor binding to the simian virus 40 early promoter.

Base Sequence↗
PubMed1996

Relative erythroid hyperplasia in the bone marrow at diagnosis of aplastic anaemia: a predictive marker for a favourable response to cyclosporine therapy.

Predicting the treatment response of aplastic anaemia (AA) is essential when considering cyclosporine (CyA) therapy among several treatment options, because it requires at least 2 months determine whether the therapy is beneficial to a patient with AA. To identify the characteristics of patients with AA who are likely to respond to CyA therapy we retrospectively reviewed the clinical records and bone marrow smears of patients treated with CyA. Among 30 patients who received the therapy for at least 3 months within 1 year after diagnosis of AA, and who had not been exposed to antilymphocyte or antithymocyte globulin, 16 (53%) responded with disease remission. CyA-responsive patients had a significantly higher ratio of erythroblasts to granulocytes (E/G ratio) in the bone marrow at the time of diagnosis as compared with patients refractory to therapy (P = 0.004). Multivariate analysis revealed that a high E/G ratio ( > 0.6) was significantly associated with a good response to CyA (P = 0.03): 15 (83%) of the 18 patients with an E/G ratio > 0.6 responded, but only one (8%) of the 12 with an E/G ratio > or = 0.6 did. Although the presence of subclinical paroxysmal nocturnal haemoglobinuria was suspected from the relative erythroblastosis observed in the bone marrow of these patients, flow cytometric analysis of neutrophils in the peripheral blood failed to reveal neutrophils deficient for glycosyl-phosphatidylinositol (GPI) anchored membrane proteins in all but one case. Identification of the presence of relative erythroid hyperplasia in he bone marrow when AA is diagnosed may help to predict a favourable response to CyA therapy, and therefore facilitate the selection of optimal therapy for AA.

Adolescent↗
PubMed2003

Establishment of human heterohybridoma and lymphoblastoid cell lines specific for the Rh D and C antigens.

Human monoclonal antibodies specific for the D antigen of the Rh system are valuable tools for blood group typing and prevention of erythroblastosis. In this study, peripheral blood lymphocytes obtained from an Rh-negative woman immunized with Rh-positive fetuses were immortalized with Epstein-Barr virus (EBV), and transformed lymphoblastoid cell lines (LCLs) secreting antibodies to Rh antigens were generated. The presence of specific antibody was assessed by direct haemagglutination using Rh-positive, papain-treated red blood cells (RBCs), and the production of human antibody was assayed by enzyme-linked immunosorbent assay (ELISA). Specificities of the antibodies were determined by a panel of RBCs of known Rh phenotypes. Five LCLs produced antibody specific for the D antigen, and one LCL showed specificity towards the C antigen of the Rh blood group system. High-titre anti-Rh antibody-producing LCLs were subsequently selected and fused with a human x mouse heteromyeloma cell line. A hybridoma line producing human antibody of the immunoglobulin M (IgM) isotype, which strongly reacted with the D antigen, was established. The hybridoma was cloned, and the monoclone has been stable for growth and antibody production during 8 months of continuous culture, with a mean antibody concentration of 11.5 microg mL-1 and haemagglutination titre of 1/20 480. This antibody was not able to agglutinate a sample of native weak D RBCs (Du); however, agglutination was achieved with papain-treated Du RBCs. Immunoprecipitation of the D antigen by this antibody, followed by Western blot analysis, did not reveal any immobilized D-specific polypeptide. As this human antibody readily agglutinates D+ RBCs in saline, it has the potential to be used as an efficient reagent in routine blood group typing.

Animals↗
PubMed2005

Hematopathologic findings in chronic idiopathic myelofibrosis.

Until now scant knowledge was available about the dynamics of chronic idiopathic myelofibrosis (CIMF). However, follow-up studies are in keeping with a stepwise evolution starting with a prefibrotic (hypercellular) phase that progressively transforms into the classical fibro-osteosclerotic endstage with myeloid metaplasia. Prefibrotic CIMF is characterized by a granulocytic and megakaryocytic myeloproliferation lacking an increase in reticulin. Most conspicuous are abnormalities of megakaryopoiesis with regard to their histotopography and maturation. There is a more than 65% probability of progression from an early to advanced CIMF accompanied by increasing anemia, splenomegaly, and leuko-erythroblastosis. A significant relationship is recognizable among frequency, tortuosity, and luminal dilation of the microvessels and the extent of myelofibrosis. Quantity of CD34(+) progenitor cells in the bone marrow (BM) reveals a close association with advancement of disease (fibrosis, splenomegaly, anemia, peripheral blasts) and therefore prognosis. Cell kinetic studies show increased proliferation associated with a higher rate of apoptosis in initial (hypercellular) stages, as well as a reduced endoreduplicative activity of megakaryopoiesis and a blocked synthesis phase of the erythroid precursors. It is noteworthy that prefibrotic and early CIMF often present with a marked thrombocytosis mimicking essential thrombocythemia. Regarding prognosis, early CIMF is associated with a significantly more favorable survival than advanced stages.

Antigens, CD34↗
PubMed1990

[Alloimmune thrombocytopenia in the newborn infant caused by maternal PlA1 antibodies].

The case of pregnant woman, whose first child was born with neonatal alloimmune thrombocytopenia (NATP) and PlA2/PlA1 constellation, is used as an example to draw up a programme for the care of pregnant women whose children are expected to be born with NATP. In one of 2,000 to one of 3,000 cases, the PlA1-positive foetal platelets cause a sensitization of the PlA1-negative mother. Transplacental passage of maternal IgG alloantibodies leads to accelerated destruction of foetal platelets. The pathophysiologic process is similar to Rh-erythroblastosis foetalis. The infants show symptoms ranging from cutaneous manifestations to intracranial haemorrhages.

Adult↗
PubMed1998

Successful fetal outcome after exposure to idarubicin and cytosine-arabinoside during the second trimester of pregnancy--a case report.

Chemotherapeutic agents administered to the mother during pregnancy may severely jeopardize the fetus. We describe a newborn girl who had been exposed to idarubicin and cytosine-arabinoside during the second and third trimesters of pregnancy due to treatment of newly diagnosed acute myeloid leukemia in the mother. The child had no structural congenital abnormalities. Adverse effects observed were prematurity, growth retardation, mildly disturbed transaminases and erythroblastosis, all of which were self-limiting with no permanent sequelae.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

The prognosis of Rh-affected pregnancies: an exception to the usual rule.

A patient with a homozygous marital partner had three progressively less seriously involved RH-positive babies after a fetal demise due to erythroblastosis. Only the first of the three required fetal transfusions. All were Rh genotypically identical. The case is presented for interest and to illustrate an exception to the usual rule.

Adult↗
PubMed1991

Neonatal consequences of placental and membrane dysfunction.

Early amnion rupture is a sporadic event that results in mechanical teratogenesis due to amniotic-band disruption and/or compression. It may cause abortion or stillbirth, craniofacial clefts, and cerebral, body wall and limb/skeletal defects. Prolonged and premature rupture of membranes and oligohydramnios result in the dry-lung syndrome and pulmonary hypoplasia. The risk of chorioamnionitis is also increased, with serious consequences to the fetus and neonate. Placental lesions are associated with fetal growth retardation, preterm birth, fetal malformations and other neonatal disorders (congenital infections, erythroblastosis, alpha thalassaemia). In particular, the impact of extremely preterm births on perinatal mortality rates and health costs is substantial. The 1-year survival rate of singleton infants born at the Monash Medical Centre was 10% at a gestation period of 23 weeks, 37% at 24 weeks, 42% at 25 weeks, 61% at 26 weeks and 78% at 27 weeks (11% at birthweights of 500-599 g, 30% at 600-699 g, 55% at 700-799 g and 71% at 800-899 g). Proven measures to minimize the neonatal consequences of extremely preterm delivery include in utero transfer of at-risk fetuses to a perinatal centre and antepartum corticosteroids. Research into the pathophysiological basis of placental and membrane dysfunction may help reduce the prematurity rate.

Adrenal Cortex Hormones↗