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PubMed1986

Cloning of the chicken progesterone receptor.

Monospecific antibodies directed against the chicken progesterone receptor (PR) form B were used to screen a randomly primed phage lambda gt11 cDNA expression library prepared from size-fractionated chicken oviduct mRNA. Two independent immunoreactive clones, lambda cPR1 and lambda cPR2, were isolated. Antibodies selected from anti-PR form B antiserum on matrices of lambda cPR1 and lambda cPR2 fusion proteins detected two proteins on electrophoretic immunoblots of crude and purified PR preparations. These proteins had the same apparent molecular weights as did PR forms A and B crosslinked with the tritiated progestin R 5020. Thus, lambda cPR1 and lambda cPR2 fusion proteins contain epitopes present in both PR forms A and B. A cDNA clone, lambda cPR3, containing the inserts of both lambda cPR1 and lambda cPR2, was isolated from a randomly primed lambda gt10 oviduct cDNA library, indicating that both cDNA inserts were derived from the same oviduct mRNA. Additional evidence that these cDNAs correspond to PR mRNA was provided by sequencing the lambda cPR3 cDNA insert, since it was found to encode the sequence of three tryptic peptides prepared from purified PR form B. A fourth and a fifth cDNA clone, lambda cPR4 and lambda cPR5, were sequentially isolated from the same lambda gt10 cDNA library beginning with a probe derived from the 3' end of the lambda cPR3 insert. Partial DNA sequencing of lambda cPR4 and lambda cPR5 revealed the presence of a sequence coding for a cysteine-rich domain that is strikingly homologous to the amino acid sequences present in the putative DNA-binding domain of the human and chicken estrogen receptors, human glucocorticoid receptor, and v-erbA gene product of the avian erythroblastosis virus.

Amino Acid Sequence↗
PubMed1987

Expression of cytoskeletal protein 4.1 during avian erythroid cellular maturation.

We have isolated a cDNA clone encoding part of protein 4.1, an integral component of the erythrocyte cytoskeleton. The recombinant was isolated by immunological screening of a chicken erythroid lambda gt11 cDNA library using a monoclonal antibody directed against protein 4.1. DNA blot analysis shows that the gene is present as a single copy per haploid chicken genome, while RNA blot analysis reveals the presence of a single mRNA of 7 kilobases in reticulocytes. Message of the same size (in reduced amounts) is also present in an erythroleukemic cell line transformed by avian erythroblastosis virus and is also present in vastly reduced quantities in nonerythroid hemopoietic cells. Immunoblotting and immunofluorescence experiments show that a subset of the chicken 4.1 variant proteins is preferentially expressed during in vitro differentiation of chicken erythroleukemic cells. These data indicate that the gene is both actively transcribed and translated during early erythroid cellular maturation.

Animals↗
PubMed1988

Human ETS2 gene on chromosome 21 is not rearranged in Alzheimer disease.

The human ETS2 gene, a member of the ETS gene family, with sequence homology with the retroviral ets sequence of the avian erythroblastosis retrovirus E26 is located on chromosome 21. Molecular genetic analysis of Down syndrome (DS) patients with partial trisomy 21 allowed us to reinforce the supposition that ETS2 may be a gene of the minimal DS genetic region. It was originally proposed that a duplication of a portion of the DS region represents the genetic basis of Alzheimer disease, a condition associated also with DS. No evidence of either rearrangements or duplications of ETS2 could be detected in DNA from fibroblasts and brain tissue of Alzheimer disease patients with either the sporadic or the familiar form of the disease. Thus, an altered ETS2 gene dosage does not seem to be a genetic cause or component of Alzheimer disease.

Alleles↗
PubMed1988

Localization of human ERBA2 to the 3p22----3p24.1 region of chromosome 3 and variable deletion in small cell lung cancer.

Human genes homologous to the v-erbA oncogene of avian erythroblastosis virus have been mapped to at least two human chromosomes. Recently, the ERBA2 gene was shown to encode a thyroid hormone receptor and localized to chromosome 3 by using flow-sorted chromosomes. We now demonstrate that this gene is located at 3p22----3p24.1, using both somatic cell hybrids and in situ hybridization studies. Since this localization is close to the distal border of the small cell lung cancer (SCLC) 3p14----3p23 deletion, we undertook additional studies to examine the ERBA2 gene in SCLC. Using somatic cell hybrids constructed from the SCLC line NCI-H182 as well as matched patient tumor and control tissue samples, we found that ERBA2 is variably deleted. Therefore, ERBA2 defines at the molecular level the distal border of the SCLC deletion and further implies that the putative suppressor gene is located centromeric of this locus. We also determined that, at least in NCI-H182, the 3p14 breakpoint is proximal to the constitutive 3p14.2 fragile site. These studies would indicate that the mechanism or initiation site of chromosomal rearrangement in SCLC is different from that which occurs during induction of the 3p14 fragile site by aphidicolin.

Carcinoma, Small Cell↗
PubMed1990

The chicken alpha-globin gene domain is transcribed into a 17-kilobase polycistronic RNA.

The 5' start sites and the 3' ends of giant transcripts of the approximately 20-kilobase (kb)-long chicken alpha-globin gene domain were identified by reverse transcription with specific primers and by nuclease S1 mapping using cloned and sequenced restriction fragments of the domain. A transcriptional unit of approximately 17 kb was found that includes all three embryonic and adult genes of the cluster. The largest transcript initiates 8 kb upstream of the gene, within a cluster of A + T-rich sequences placed upstream of a matrix attachment point, at one of several CAA(A)T boxes framing a cluster of four TATA boxes. The 5' ends of a group of 2.5-, 5-, and 12-kb globin transcripts accumulating in avian erythroblastosis virus-transformed cells, which transcribe globin genes abortively, map to the sequence ATATATAATAA 1 kb upstream of the embryonic pi-globin gene. This sequence might correspond to a site of RNA processing or of alternative transcription initiation. Transcription of the domain ends about 2 kb downstream of the last gene of the cluster, downstream of an enhancer and immediately upstream of a CR1 repetitive element in an A + T-rich sequence that includes a matrix attachment site. These data indicate that full-domain transcripts including embryonic as well as adult alpha-globin genes exist, and that the region transcribed is framed by A + T-rich linkers and matrix attachment points.

Animals↗
PubMed1990

Activation of erythropoietin receptors by Friend viral gp55 and by erythropoietin and down-modulation by the murine Fv-2r resistance gene.

The leukemogenic membrane glycoprotein (gp55) encoded by Friend spleen focus-forming virus appears to bind to erythropoietin receptors (EpoR) sto stimulate erythroblastosis [Li, J.-P., D'Andrea, A.D., Lodish, H.F. & Baltimore, D. (1990) Nature (London) 343, 762-764]. To directly compare the effects of gp55 with erythropoietin (Epo), we produced retrovirions that encode either gp55, Epo, or EpoR. After infection with EpoR virus, interleukin 3-dependent DA-3 cells bound 125I-labeled Epo and grew without interleukin 3 in the presence of Epo. These latter cells, but not parental DA-3 cells, became factor-independent after superinfection either with Epo virus or with Friend spleen focus-forming virus. In addition, Epo virus caused a disease in mice that mimicked Friend erythroleukemia. Although Fv-2r homozygotes are susceptible to all other retroviral diseases, they are resistant to both Epo viral and Friend viral erythroleukemias. These results indicate that both gp55 and Epo stimulate EpoR and that the Fv-2 gene encodes a protein that controls response to these ligands. However, the Fv-2 protein is not EpoR because the corresponding genes map to opposite ends of mouse chromosome 9. These results have important implications for understanding signal transduction by EpoR and the role of host genetic variation in controlling susceptibility to an oncogenic protein.

Animals↗
PubMed1993

A hepatitis B virus pre-S-retinoic acid receptor beta chimera transforms erythrocytic progenitor cells in vitro.

In this report, we investigated the transforming properties of retinoic acid receptor beta (RAR beta). The v-erbA protein, which is the viral oncogenic homologue of the thyroid hormone receptor, was replaced by either the complete RAR beta (beta R) or a hepatitis B virus pre-S-RAR beta (H beta R) hybrid product in an avian erythroblastosis virus-based vector. In chicken hematopoietic cells, the H beta R protein was able to transform erythroid progenitor cells, whereas no such transformation was observed with the wild-type beta R protein. Moreover, the fully transformed phenotype was observed even in the absence of v-erbB, and H beta R-transformed erythroid cells grew independently of growth factors and transforming growth factor alpha. The analysis of erythrocytic-specific proteins revealed that the transformed cells were blocked at the colony-forming unit-erythroid stage and that the expression of the carbonic anhydrase II gene, a gene normally regulated by thyroid hormones, was repressed by the H beta R protein. Finally, hepatocarcinomas rapidly developed in some chickens infected in ovo with viruses encoding either the normal or the hybrid H beta R, suggesting that an inappropriate expression of the RAR beta gene may represent an important event in oncogenesis.

Amino Acid Sequence↗
PubMed1993

The protooncogene c-sea encodes a transmembrane protein-tyrosine kinase related to the Met/hepatocyte growth factor/scatter factor receptor.

c-sea is the cellular homologue of the avian erythroblastosis virus S13-encoded oncogene v-sea. We have isolated and determined the nucleotide sequence of overlapping chicken cDNAs that encode the putative c-sea protooncogene product. The predicted reading frame encoded a 1404-aa polypeptide that had the structure of a receptor-like protein-tyrosine kinase and exhibited the highest degree of sequence similarity with the Met/hepatocyte growth factor/scatter factor receptor. Analysis of steady-state RNA expression revealed that c-sea mRNA levels were elevated approximately 5-fold in chicken embryo cells transformed by activated variants of the src nonreceptor protein-tyrosine kinase gene but not in cells transformed by the nuclear oncogenes v-myc or v-rel. A survey of c-sea expression in a variety of chicken tissues indicated that the highest levels of mRNA were located in peripheral white blood cell populations and in the intestine.

Amino Acid Sequence↗
PubMed1993

v-jun cooperates with v-erbB to transform the thrombocytic/megakaryocytic lineage.

The transforming properties of v-jun, the viral counterpart of the transcription factor AP1, were investigated in avian hematopoietic cells. Two retroviruses, called JB and JBN, expressing both v-jun and v-erbB, were constructed using an avian erythroblastosis-based vector. We show that the cooperative action of both oncogenes allowed the virus to efficiently transform bone marrow cells. No such transformation was obtained with either oncogene alone. JB-transformed bone marrow cells expressed GATA-1, TAL-1, and histone H5, suggesting that they belong to the erythrocytic/thrombocytic lineage. (Thrombocytes are the avian homologues of mammal megakaryocytes.) Moreover, after induction with phorbol 12-myristate 13-acetate JB-transformed bone marrow cells began to differentiate and synthesized high levels of platelet glycoproteins, indicating that they were of thrombocytic origin. These results were confirmed by c-ets1 analysis since this transcription factor, specifically found in cells with megakaryocytic but not erythrocytic features, was clearly detected in these cells.

Animals↗
PubMed1993

Identification of a domain required for oncogenic activity and transcriptional suppression by v-erbA and thyroid-hormone receptor alpha.

v-erbA, a mutated version of the chicken thyroid hormone (TH) receptor type alpha, can inhibit hormonal induction of target genes. In addition, v-erbA acts as a constitutive repressor of the basal promoter activity. In vivo, v-erbA can arrest the differentiation of erythroid precursor cells and suppresses transcription of erythrocyte-specific genes. We show that the v-erbA protein of the transformation-defective avian erythroblastosis virus mutant (AEVtd359) fails to suppress basal transcription level and exhibits impaired ability in antagonizing the TH and retinoic acid response. The inactivating mutation is a 1-nt change leading to a Pro-->Arg replacement in the "hinge region" of v-erbA protein. Introducing this mutation in the context of TH receptor alpha selectively inactivates the suppressor function, while hormone-binding and transcriptional-activation properties are unaffected. These data suggest that trans-repression rather than a dominant negative block of TH-receptor or retinoic acid-receptor activation may represent the primary molecular property underlying erbA oncogenesis.

Alpharetrovirus↗
PubMed1993

Expression of a constitutively active erythropoietin receptor in primary hematopoietic progenitors abrogates erythropoietin dependence and enhances erythroid colony-forming unit, erythroid burst-forming unit, and granulocyte/macrophage progenitor growth.

We tested the ability of a constitutively activated erythropoietin receptor [EpoR(R129C)] to alter the growth requirements of primary hematopoietic precursors that terminally differentiate in culture. Two recombinant retroviruses expressing EpoR(R129C), spleen focus-forming virus (SFFVc-EpoR) and myeloproliferative sarcoma virus (MPSVcEpoR), were used to infect fetal liver cells that served as a source of hematopoietic progenitors. Methylcellulose cultures were incubated in the absence of any added growth factors or in combination with selected growth factors. EpoR(R129C) completely abrogated the Epo requirement of erythroid colony-forming units to form erythrocytes after 2-5 days in culture and did not interfere with the differentiation program of these cells. In the absence of added growth factors EpoR(R129C) did not enhance erythroid burst-forming unit development. In contrast to experiments in heterologous cell lines, EpoR(R129C) did not render progenitor cells independent of interleukin 3 or granulocyte/macrophage colony-stimulating factor (GM-CSF). However, when progenitors were cultured with added steel factor, but not with interleukin 3 or GM-CSF, EpoR(R129C) augmented the growth and differentiation of erythroid bursts, mixed erythroid/myeloid, and granulocyte/macrophage (GM) colonies. Furthermore, both viruses were capable of expressing EpoR(R129C) in erythroid, mixed erythroid/myeloid, and GM colonies. Thus an aberrantly expressed and constitutively activated EpoR can stimulate proliferation of some GM progenitors. The ability of EpoR(R129C) to abrogate the Epo requirement of primary hematopoietic cells, but not the requirement for other cytokines, is consistent with the induction of erythroblastosis in vivo.

Animals↗
PubMed1997

A transformation-associated complex involving tyrosine kinase signal adapter proteins and caldesmon links v-erbB signaling to actin stress fiber disassembly.

The avian erythroblastosis viral oncogene (v-erbB) encodes a receptor tyrosine kinase that possesses sarcomagenic and leukemogenic potential. We have expressed transforming and nontransforming mutants of v-erbB in fibroblasts to detect transformation-associated signal transduction events. Coimmunoprecipitation and affinity chromatography have been used to identify a transformation-associated, tyrosine phosphorylated, multiprotein complex. This complex consists of Src homologous collagen protein (Shc), growth factor receptor binding protein 2 (Grb2), son of sevenless (Sos), and a novel tyrosine phosphorylated form of the cytoskeletal regulatory protein caldesmon. Immunofluorescence localization studies further reveal that, in contrast to the distribution of caldesmon along actin stress fibers in normal fibroblasts, caldesmon colocalizes with Shc in plasma membrane blebs in transformed fibroblasts. This colocalization of caldesmon and Shc correlates with actin stress fiber disassembly and v-erbB-mediated transformation. The tyrosine phosphorylation of caldesmon, and its association with the Shc-Grb2-Sos signaling complex directly links tyrosine kinase oncogenic signaling events with cytoskeletal regulatory processes, and may define one mechanism regulating actin stress fiber disassembly in transformed cells.

Actins↗
PubMed2000

Genetic restriction of HIV-1 pathogenesis to AIDS by promoter alleles of IL10.

IL10 is a powerful TH-2 cell cytokine produced by lymphoid cells that limits HIV-1 replication in vivo, ostensibly by inhibiting macrophage/monocyte and T-cell lymphocyte replication and secretion of inflammatory cytokines (IL1, TNFalpha, IL6, IL8, and IL12). A genetic epidemiological scan of patients enrolled in AIDS cohorts for candidate gene-linked short tandem repeat polymorphisms revealed significant genotype associations for HIV-1 infection and progression to AIDS with markers adjacent to and tracking (by linkage disequilibrium) common single nucleotide polymorphic variants in the IL10 promoter region. Individuals carrying the IL10-5'-592A (IL10-5'A) promoter allele possibly were at increased risk for HIV-1 infection, and once infected they progressed to AIDS more rapidly than homozygotes for the alternative IL10-5'-592 C/C (IL10-+/+) genotype, particularly in the later stages of HIV-1 infection. An estimated 25-30% of long-term nonprogressors (who avoid clinical AIDS for 10 or more years after HIV-1 infection) can be attributed to their IL10-+/+ promoter genotype. Alternative IL10 promoter alleles are functionally distinct in relative IL10 production, in retention of an avian erythroblastosis virus transcription factor recognition sequence and in binding to specific putative nuclear transcription factors, suggesting a potential mechanism whereby IL10-5'A down-regulation of inhibitory IL10 facilitates HIV-1 replication in vivo, accelerating the onset of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1999

The tyrosines in the bidentate motif of the env-sea oncoprotein are essential for cell transformation and are binding sites for Grb2 and the tyrosine phosphatase SHP-2.

The transforming gene product of the S13 avian erythroblastosis virus, the env-sea protein, is a member of the hepatocyte growth factor receptor family of tyrosine kinases comprising Met, Ron, and Sea. Like all three members of this family, the env-sea protein has a so-called bidentate motif (Y557INMAVTY564VNL) composed of two tandemly arranged tyrosines in the carboxyl terminus. To investigate whether the tyrosine residues in this motif are essential for the env-sea-mediated transformation, we generated tyrosine to phenylalanine mutations. Substitutions of both tyrosine residues resulted in complete loss of the transforming activity. In contrast, single mutations at either tyrosine did not inhibit transformation of Rat1 cells, and mutation of tyrosine 564 actually increased transformation of Rat 1 cells. To define signaling pathways activated by the env-sea protein, we looked for protein-protein interactions mediated by these tyrosine residues. We show that the bidentate motif is responsible for interaction with the adapter protein Grb2, phosphatidylinositol 3-kinase, and the tyrosine phosphatase SHP-2. Furthermore, we show that microinjected Src homology 2 domains from either Grb2 or SHP-2 blocked the transforming activity of the env-sea protein. Together, these results suggest that the tyrosines within the bidentate motif are essential for the env-sea transformation.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Structural analysis of the autoinhibition of Ets-1 and its role in protein partnerships.

The DNA-binding activity of the eukaryotic transcription factor Ets-1 (E26 avian erythroblastosis virus oncogene-E twenty-six) is negatively regulated by inhibitory regions that flank the ETS domain. Based on the results of solution studies, these N- and C-terminal inhibitory regions have been proposed to pack against the ETS domain and form an autoinhibitory module whose N terminus partially unfolds upon binding of Ets-1 to DNA. Mutations that disrupt autoinhibition of DNA binding also cause a structural change in the inhibitory region. We report here a crystallographic study of fragments of Ets-1 that provide structural details of the inhibitory module and the structural transition that accompanies DNA binding. The structures of free and DNA-bound Ets-1 fragments containing the ETS domain and the inhibitory regions confirm that the N-terminal inhibitory region contains two alpha-helices one of which unfolds upon Ets-1 binding to DNA. The observations from the crystal structure, coupled with mutagenesis experiments, allow us to propose a model for the inhibited form of Ets-1 and lend insight into the flexible interaction between Ets-1 and the acute myeloid leukemia 1 protein, AML1 (RUNX1).

Binding Sites↗
PubMed1991

RRR-alpha-tocopheryl succinate enhances T cell mitogen-induced proliferation and reduces suppressor activity in spleen cells derived from AEV-infected chickens.

RRR-alpha-tocopheryl succinate was demonstrated to be a potent in vitro modulator of retrovirus-induced immune abnormalities. Spleen cells from avian erythroblastosis virus (AEV)-infected chickens exhibit suppressed T cell mitogen-induced proliferative responses and elevated levels of suppressor T cell activity. In vitro addition of RRR-alpha-tocopheryl succinate resulted in amelioration of these abnormalities. Antioxidants including Trolox (a water-soluble analogue of RRR-alpha-tocopherol with antioxidant properties) and a combination of butylated hydroxyanisole and butylated hydroxytoluene were able to restore immune functions to levels similar to those achieved with RRR-alpha-tocopheryl succinate treatment. Aspirin, an irreversible inhibitor of cyclooxygenase activity, was capable of ameliorating some of the AEV-induced immune dysfunctions. These studies suggest a role for the antioxidant functions of RRR-alpha-tocopheryl succinate in modulation of retrovirus-induced immune abnormalities.

Alpharetrovirus↗
PubMed1993

Effects of RRR-alpha-tocopheryl succinate on IL-1 and PGE2 production by macrophages.

Vitamin E is thought to enhance immunity by increasing interleukin-1 (IL-1) production and by downregulating prostaglandin E2 (PGE2) synthesis. In an effort to understand the mechanism(s) whereby the form of vitamin E known as RRR-alpha-tocopheryl succinate [also called vitamin E succinate (VES)] ameliorates retrovirus-induced immune dysfunctions, peritoneal exudate cells (PECs) derived from normal chickens and avian and murine macrophage cell lines were used as in vitro model systems to test the effects of VES treatments on PGE2 and IL-1 production. Supernatants from PECs that were exposed to avian erythroblastosis virus (AEV) for 45 minutes exhibited a 256% increase in PGE2 levels compared with supernatants from replica cultures of PECs not exposed to AEV. Pretreatment of PECs with VES before exposure to AEV maintained PGE2 levels at normal control levels. VES treatment enhanced IL-1 production by avian (HD11) and murine (P388D1) macrophage cells, respectively. Supernatants from VES-treated HD11- and P388D1-stimulated cells contained IL-1 activity 196% and 385%, respectively, greater than that observed with supernatants from untreated control cells. On the basis of these studies, downregulation of retrovirus-induced PGE2 production and/or upregulation of IL-1 production by VES are potential mechanisms for VES amelioration of retrovirus-induced immune suppression.

Animals↗
PubMed2003

Myelofibrosis after essential thrombocythemia complicated by alveolar proteinosis.

Hematological diseases are often accompanied by respiratory disorders. Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by excessive accumulation of surfactant in the alveolar space. We describe a case of PAP complicated by myelofibrosis following essential thrombocythemia. The patient developed high fever, respiratory failure, and leuko-erythroblastosis during the progressive course of PAP. These symptoms were alleviated by prednisolone. The level of serum IL-6 was elevated when PAP was progressing rapidly. This may explain why the symptoms were alleviated by the steroids.

Bone Marrow↗