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The 22-d orbital flight of rats onboard the Cosmos-605 biosatellite was followed by inhibition of erythroblastosis, alteration in the morphology of megakaryocytes, and stimulation of myelopoiesis. These changes returned to normal 27 d postflight. The colony-forming capacity and pattern of differentiation of hemopoietic stem cells of bone marrow of flight rats remained undisturbed.
The carbonic anhydrase II (CAII) gene is the only known gene identified as direct target for v-ErbA-mediated repression in avian erythroleukemic cells transformed by Avian Erythroblastosis Virus (AEV). This gene is transcriptionally activated by thyroid hormone (T3) in normal erythrocytic cells. In this work we have analysed the molecular basis of the transcriptional control of the CAII gene by c-ErbA and v-ErbA. We show that several domains in the promoter control hormonal regulation of transcription. One domain proximal to the TATA box mediates T3 response but contains no identified binding site for c-ErbA. An other domain termed PAL2 is approximately 600 bp upstream the transcription initiation site and contains a c-ErbA binding site. We show that when it is associated to a heterologous promoter this site mediates transcriptional repression in erythrocytic cells but not in HeLa cells. Moreover, this site binds a nuclear erythrocyte-specific factor that we called NFX, which is different from c-ErbA. heterodimers between c-ErbA and the 9-cis retinoic acid receptor (RXR) compete with NFX for binding to PAL2. In contrast, v-ErbA alone or in association with RXR is a very poor competitor and is unable to chase NFX out of the PAL2 site. We propose that NFX is a transcription repressor whose activity is inhibited by c-ErbA but not v-ErbA. This mechanism might contribute to the overall regulation of the carbonic anhydrase II promoter. These data illustrate another possible mechanism through which v-ErbA might antagonize the function of c-ErbA in controlling gene expression.
The identification of thyroid hormone as an endogenous signal for erythroid differentiation began with our studies on the spontaneously differentiating murine erythroleukemia clone 3-1. We observed that the spontaneous differentiation frequency was dependent on a heat stable factor present in fetal calf serum or calf bone marrow. We also noted that the bone marrow extract stimulated erythroid colony-forming units in mouse bone marrow cells, suggesting the relevance of this factor in normal erythroid differentiation. The bone marrow extract did not supplant the requirement of erythropoietin but was synergistic. Purification of the bone marrow extract indicated that the differentiation-inducing activity for clone 3-1 cells cochromatographed with a low-molecular-weight, UV (280 nm)-absorbing component(s). These observations and previous reports identifying the avian erythroblastosis virus oncogene v-erbA as a mutated thyroid hormone receptor which blocked erythroid differentiation led us to test thyroid hormone in our assay. Both triiodothyronine and thyroxine were highly active, and the active constituents in the chromatographically purified fraction were identified as triiodothyronine and thyroxine. Although thyroid hormone action has been associated with both in vivo and in vitro erythroid differentiation, its role has been often relegated to a secondary status. We suggest that thyroid hormone is required for the commitment of erythroid cells to terminal differentiation.
The v-erbB protein encoded by the avian erythroblastosis virus AEV-H is responsible for the transformation of fibroblasts and erythroblasts by this virus. Deletion of amino acids 961-1102, which lie carboxy terminal to the kinase domain of the v-erbB protein, destroys the ability of the virus to transform erythroid cells without severely affecting fibroblast transformation. This region is termed the E-domain and has been postulated to contain a region important for erythroid cell transformation. In-frame deletions of approximately 23 amino acids were introduced throughout the E-domain in an attempt to locate a specific region that was essential for erythroid cell transformation. Several of the deletions gave rise to a partial transformed phenotype, although no single deletion that completely abolished erythroid cell transformation was found. Interestingly, deletion of amino acids 1031-1055 resulted in a superactivated v-erbB protein that was more active for erythroid cell transformation than the wild-type AEV-H v-erbB protein. This indicates that there is a negative regulatory region located within this region that normally partially suppresses the transforming activity of the v-erbB protein for erythroid cells. These data suggest that the E-domain contains both negative and positive regulatory regions that function in erythroid cells, and complete deletion of the region is necessary to abolish erythroid cell transformation.
Based on homology to the tyrosine kinase domain of the chick erythroblastosis virus oncogene v-sea, we cloned a cDNA encoding a novel receptor tyrosine kinase from a human hepatoma HepG2 cDNA library. The encoded protein, which we termed 'Sky', contains an intracellular tyrosine kinase domain and a unique extracellular domain with two immunoglobulin (Ig)-like domains and two fibronectin type III (FN III) domains. The overall structure of Sky is homologous to the reported sequence of the oncogenic Axl/Ufo receptor tyrosine kinase. Phylogenetic analysis in the tyrosine kinase domain shows that Sky, Axl/Ufo, Ark, and v-Ryk form a sub-family distinct from other tyrosine kinases. Northern blot analysis revealed that sky mRNA is expressed predominantly in brain and faintly in tissues of other organs. As the combination of Ig-like and FN III domains is often observed in neural cell adhesion molecules and receptor protein tyrosine phosphatases, Sky may be involved in cell adhesion processes, particularly in the central nervous system.
ets-1 and ets-2 genes have previously been identified by their sequence homology to the v-ets oncogene of the avian erythroblastosis virus, E26. These cellular genes have been shown to function as transcription factors important in lymphoid differentiation and activation and cellular proliferation. In this study, we have broadly analysed the differential expression of ets-1 and ets-2 during murine development using in situ hybridization. Our results indicate that these transcription factors are expressed in multiple tissues during critical stages of embryo formation and organogenesis, suggesting that these genes may serve multiple functions during mouse development. The patterns of expression of both genes are quite different as early as day 8.0 of gestation. ets-1 expression is clearly observed during a narrow developmental stage in the developing nervous system, including the presumptive hindbrain regions, the neural tube, as well as neural crest and the first and second branchial arches, ets-2 expression is limited to the developing limb buds and distal tail. At later times, ets-1 expression is observed in developing vascular structures, including the heart, arteries, capillaries and meninges, whereas ets-2 is highly expressed in developing bone, tooth buds, epithelial layers of the gut, nasal sinus and uterus, and several regions of the developing brain. Both ets-1 and ets-2 are expressed in developing lung, gut and skin. High levels of expression in both genes is observed in adult lymphoid tissues, but in different tissue subsets. ets-1 is expressed in the adult lung, gut mesenchyme and bone marrow. ets-2 continues to be expressed at low levels in several adult tissues, except in the differentiated brain, where substantial levels of expression are found in particular regions of the mature brain. These results demonstrate that ets-1 and ets-2 are differentially regulated, are widely expressed in many tissues during murine embryogenesis and may play important roles in cellular proliferation and differentiation during mouse development.
HL60 cells are devoid of endogenous epidermal growth factor receptor (EGFR). They respond to retinoic acid and undergo terminal granulocytic differentiation. EGFR complementary DNA was introduced into HL60 cells by retroviral gene transfer. Scatchard plot showed that the binding characteristics are identical to those of A431 cells. HL60-EGFR cells were estimated to express 34,000 EGFR/cell (Kd = 5 nM). The tyrosine phosphorylation upon ligand binding is the first step of signal transduction. The dominant phosphotyrosyl proteins in epidermal growth factor-stimulated HL60-EGFR cells include a 170 kDa protein (EGFR itself), and 125 and 53 kDa proteins. The EGFR signal results in the induction of 92 kDa gelatinase/matrix metalloproteinase in HL60-EGFR cells, thereby providing evidence of the function of the exogenous EGFR and a semiquantitative measure of the EGFR signal. These HL60-EGFR cells offer a unique opportunity to examine the potentially important role of EGFR (c-erbB) in maintaining homeostasis between self-renewal and differentiation. c-erbB has been shown to play a physiological role in the self-renewal of the very early avian stem cells which do express EGFR. The v-erbB (double truncated EGFR) has been shown to cause avian erythroblastosis. We found that these HL60-EGFR cells responded to retinoic acid differently from the HL60-control cells. A partial block of only 45% granulocytic differentiation and concomitant proliferation was noted, consistent with a shift of balance between self-renewal and differentiation toward the former.
We sought to identify the significance of recurrent stillbirth and to determine the contributory etiologic factors for this phenomenon. Data were analyzed and retrospective chart review conducted for all stillbirths occurring during a 13-year period. Subjects were divided into two groups: those for whom the current stillbirth was the first and those who had had a previous stillbirth. The study included 48,479 consecutive multiparous women, of whom 403 had delivered stillborn infants (8.31/1,000 live births). For 34 of these subjects, this represented a recurrent stillbirth (84.36/1,000 live births). The recurrent-stillbirth group had a 10.15-fold higher risk for stillbirth. Additionally, this group had a twofold higher incidence of diabetes and hypertensive disease than did those women experiencing their first stillbirths; furthermore, the gestational age and birth weight of the stillborn infants were significantly lower in the recurrent-stillbirth group (P < .0004 and < .007, respectively). Such factors as socioeconomic class, chorioamnionitis and erythroblastosis fetalis, traditionally cited as contributing to repeated fetal loss, were not significant. Although recurrent stillbirth remains an unsolved problem, improving health care to specific groups within high-risk populations may reduce fetal loss.
The S13 avian erythroblastosis viral genome encodes an oncogenic tyrosine kinase, termed env-sea, that is capable of transforming fibroblasts and erythroblasts. Although the tyrosine kinase activity of the env-sea protein has been shown to be necessary for transformation, no substrates for this enzyme have been detected in vivo. Here we demonstrate that the recently described shc proteins are phosphorylated on tyrosine residues in both S13 transformed fibroblasts and erythroblasts. Furthermore, using an S13 temperature sensitive mutant, we show that the phosphorylation of the shc proteins occurs concomitantly with the activation of the tyrosine kinase activity of the env-sea protein. These observations make the phosphorylation of the shc proteins a good candidate for being involved in oncogenic signaling by the env-sea oncoprotein.
Splenic rupture is a rare cause of hemoperitoneum in the neonate. We report on a case of splenic rupture in a full-term neonate with normal spleen following a non-traumatic delivery. The spleen was found to be completely transected and a splenectomy was required. Several etiologies have been proposed: traumatic delivery, in utero fetal trauma prior to delivery, high birth weight, clotting defect, erythroblastosis fetalis. Partial splenectomy or repair of splenic laceration should be performed rather than total splenectomy which can cause severe bacterial sepsis.
The transforming gene product of the S13 avian erythroblastosis virus, env-sea, is a member of the growth factor receptor class of tyrosine kinases. The env-sea precursor protein gp155env-sea is proteolytically processed into the mature cleavage products gp85env-sea and gp70env-sea which are subsequently terminally glycosylated. Previous studies have shown that the abnormal glycosylation of gp155env-sea which takes place in the presence of the inhibitor castanospermine inhibits the proteolytic cleavage of gp155env-sea and blocks its transforming ability. To define a role for proteolytic processing of env-sea in transformation, we have introduced mutations at the protease recognition site which efficiently block cleavage without affecting the biosynthesis or transport of the resulting uncleaved protein. We show here that an uncleaved but fully glycosylated sea-encoded protein retains the ability to transform chicken embryo fibroblasts, indicating that proteolytic processing is not essential for transformation by the env-sea tyrosine kinase.
OBJECTIVE: To determine whether there is an association between parvovirus B19 infection and early spontaneous abortion at less than 20 weeks' gestation. METHODS: Eighty samples of early spontaneous abortions were analyzed. Each sample was examined histologically for the presence of viral inclusions, and selected cases were analyzed for parvovirus using electron microscopy and in situ hybridization. Polymerase chain reaction DNA amplification for the virus was done in each case. Maternal sera were analyzed for immunoglobulin (Ig) M and IgG parvovirus antibodies and compared with temporally matched controls. RESULTS: Five cases in the study group had evidence of seroconversion for parvovirus, compared with two controls. Products of conception from two of these five cases were positive for virus by polymerase chain reaction amplification, and only one of these two had a characteristic inclusion of parvovirus histologically. Conversely, five chorionic vesicles from mothers who had not seroconverted had histologic changes suggesting parvovirus infection, but all of these cases were negative for parvovirus using in situ hybridization, polymerase chain reaction, and electron microscopy. CONCLUSIONS: Parvovirus B19 DNA was found in two of 80 early spontaneous abortuses. Although viral DNA was detected in two cases, there was no clear evidence that the infections caused fetal death. Neither case showed erythroblastosis with large numbers of inclusions, as is seen in hydropic fetuses with parvovirus infection. In addition, in five cases in which parvovirus infection was not documented serologically or by the polymerase chain reaction, there was erythroid nuclear clearing suggestive of parvovirus B19 inclusions. This indicates that histologic evaluation for parvoviral inclusions is not always reliable in early spontaneous abortuses.
The transforming gene product of the S13 avian erythroblastosis virus, env-sea, is a member of the growth factor receptor class of tyrosine kinases. The env-sea precursor protein gp155env-sea is proteolytically processed into the mature cleavage products gp85env and gp70env-sea, which are subsequently terminally glycosylated and transported to the cell surface. Previous studies have shown that the abnormal glycosylation of gp155env-sea induced by the carbohydrate processing inhibitor castanospermine blocks the proteolytic cleavage of gp155env-sea and impairs its transforming ability. We have shown recently that an uncleaved but fully glycosylated sea-encoded protein retains the ability to transform chicken embryo fibroblasts, indicating that proteolytic processing is not essential for transformation by the env-sea tyrosine kinase. To address the question of how castanospermine blocks transformation by env-sea, differential sucrose gradient centrifugation was performed on env-sea-transformed cells treated with the inhibitor. This report shows that no surface forms of env-sea could be detected in inhibitor-treated cells, suggesting that castanospermine acts by blocking the transport of sea-encoded proteins to the cell surface.
We have compared the long-term stability of 2 avian non-replicative retroviral vectors in an infected permanent cell line from quail fibroblasts (QT6). Vectors NL53 and NPL, expressing both the neo and LacZ genes under control of cis-acting elements originated from avian erythroblastosis virus (AEV), are similar to each other except for the presence of the phleomycin-resistance SHble gene fused upstream the reporter LacZ gene, in NPL vector. The use of such vectors, with an uniform backbone, to infect QT6 cells, allowed us to demonstrate that stability of the beta-galactosidase activity encoded by the SHble-LacZ fusion gene remains higher than that encoded by the native LacZ gene, as determined in the same conditions of culture. Moreover, stability of the provirus was dependent on the selection pressure. Here we show that stability of beta-galactosidase activity in infected QT6 cells was obtained with high dose selection for the selectable SHble-LacZ fusion gene.
The paper describes events that in the last fifteen years, have led to the identification of the aetiological agents of three widely known diseases: cat scratch disease, erythema infectiosum and exanthem subitum. The particular features of Afipia felis and Rochalimaea, Parvovirus B 19 and Herpesvirus 6 are presented. The paternity of new diseases (i.e. bacillary angiomatosis, bacillary peliosis hepatitis, LES-like syndrome, chronic fatigue syndrome, petechial glove and sock syndrome, etc.) has also been attributed to some of these pathogens as has the paternity of some older ones (i.e. aplastic crisis, erythroblastosis fetalis, trench fever, hepatitis, opportunistic infection, etc.). It has been argued that the same pathogen can cause different diseases depending on the immunogenic state of the subject. To date, persisting difficulties in isolating the pathogen or differentiating between latent or active infection, still in some cases raises doubts concerning the attribution of the disease to a specific agent. New immunological or molecular techniques, allowing the direct detection of in vivo replication, are still needed in order to establish a sure connection between some of these agents and some of these diseases. Progress here will both give more accurate data about the epidemiology of some diseases and allow us to apply more appropriate treatment and prevention techniques.
The purpose of this study was to evaluate the significance of histological examination of the placenta during routine post-mortem examination of foetal, perinatal and early neonatal deaths with particular reference to the cause of death. Three hundred (300) placentas were examinated over a period of three years (1988-1991). The clinical history, autopsy examination and placental histological examination were taken into account to determine the cause of death. Autopsy findings revealed the cause of death in only 33 cases (12.9%). In contrast, placental examination allowed us to determine the cause of death in 123 cases (48.4%) especially in abortions (54.4%). The most frequent abnormalities found were vascular insufficiency in intrauterine deaths (16.47%) and acute chorioamnionitis with foetal involvement in abortions (31.4%). Fifty six (56) cases with diagnoses of acute chorioamnionitis, chronic villitis of unknown aetiology and erythroblastosis were classified in the highrisk group for a subsequent pregnancy. Routine histological examination of the placenta following a perinatal death constitutes a necessary complement to autopsy examination, as it provides essential information for the cause of death and therefore helps in planning and more effective prenatal monitoring of a future pregnancy.
The heart is a major target organ for thyroid hormone action, and marked changes occur in cardiac function in patients with hypothyroidism or hyperthyroidism. Triiodothyronine (T3)-induced changes in cardiac function can result from direct or indirect T3 effects. Direct T3 effects result from T3 action in the heart itself and are mediated by nuclear or extranuclear mechanisms. Extranuclear T3 effects, which occur independently of nuclear T3 receptor binding and increases in protein synthesis, influence primarily the transport of amino acids, sugars, and calcium across the cell membrane. Nuclear T3 effects are mediated by the binding of T3 to specific nuclear receptor proteins, which results in increased transcription of T3-responsive cardiac genes. The T3 receptor is a member of the ligand-activated transcription factor family and is encoded by cellular erythroblastosis A (c-erb A) genes. T3 increases the heart transcription of the myosin heavy chain (MHC) alpha gene and decreases the transcription of the MHC beta gene, leading to an increase of myosin V1 and a decrease in myosin V3 isoenzymes. Myosin V1, which is composed of two MHC alpha, has a higher myosin ATPase activity than myosin V3, which contains two MHC beta. The globular head of myosin V1, with its higher ATPase activity, leads to a more rapid movement of the globular head of myosin along the thin filament, resulting in an increased velocity of contraction. T3 also leads to an increase in the speed of diastolic relaxation, which is caused by the more efficient pumping of the calcium ATPase of the sarcoplasmic reticulum (SR). This T3 effect results from T3-induced increases in the level of the mRNA coding for the SR calcium ATPase protein, leading to an increased number of calcium ATPase pump units in the SR. Overall, T3 leads to an increase in ATP consumption in the heart. In addition, less chemical energy of ATP is used for contractile purposes and more of it goes toward heat production, which causes a decreased efficiency of the contractile process in the hyperthyroid heart. The pathophysiologic basis for myxedema is the opposite of that discussed for the hyperthyroid heart. In addition to decreased direct effects of thyroid hormone in cardiac myocytes, indirect effects occur through decreases in peripheral oxygen consumption and changes in hemodynamic parameters. Myofibrillar swelling with loss of striation and interstitial fibrosis occurs on histologic examination of hypothyroid hearts. In addition, accumulation of mucopolysaccharide substances (Glycosaminoglycans) can be demonstrated. On electron microscopic examination, mitochondria show disruption and lipid inclusion. Cardiac papillary muscle obtained from animals with hypothyroidism shows a depression of the force velocity curve and reduced rate of tension development, indicating significant contractile abnormalities. In patients with hypothyroidism, a true enhanced incidence of hypertension (increased peripheral vascular resistance) has been found. In addition, hypercholesterolemia and impairment of fatty acid mobilization are associated with myxedema and present additional risk factors for the development of atherosclerotic cardiovascular disease.
First member of Ets gene family was discovered a decade ago by studying avian erythroblastosis virus, E26. This virus encodes a tripartite protein gag-myb-ets with a molecular weight of 135 kDa. Subsequently, a series of cellular Ets genes were isolated (Ets-1, Ets-2, Erg, Elk-1, Sap-1, PEA-3, PU.1, Fli-1, Pok/Yan, Etv-1 etc.). These genes share sequence homology to E26 Ets gene (v-ets or viral ets). Ets genes are highly conserved in phylogenetically divergent species from Drosophila to man. Mammalian Ets genes are located on different chromosomes. Ets gene products are transcriptionally active sequence-specific DNA binding proteins and are differentially regulated. Ets genes are involved in certain chromosomal translocations leading to the formation of chimeric fusion proteins that are associated with certain leukemias and soft tissue cancers. Ets genes also have a role in T-cell development and molecular and genetic analysis of Down Syndrome patients have implicated the human Ets-2 and Erg genes in the disease. Down Syndrome afflicted patients have immunologic and thymic disorders as well as a greater risk for leukemic disease. Thus, Ets genes having homology to viral oncogenes, may be instrumental in regulating cellular growth and differentiation, as well as organismal development. Alteration of these genes and their products may cause deregulation of normal cell growth and differentiation and result in a disease.