Gene/Protein Disease Symptom Drug Enzyme Compound
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A large number of novel cellular proto-oncogenes have been identified and cloned by analysis of common integration sites in retrovirally induced malignancies. In the multistage erythroleukemias induced by the various strains of Friend leukemia virus, the analysis of proviral-integration events has led to the identification of two genes, Fli-1 and Spi-1, both novel members of the ets oncogene family of transcription factors. In this report, we describe the identification of another integration site, designated Fli-2 (Friend leukemia virus integration-2), in an erythroleukemia cell line induced by Friend murine leukemia virus (F-MuLV). Rearrangements at the Fli-2 locus were found in two erythroleukemia cell lines independently induced by F-MuLV and one leukemic cell line derived from the spleen of a mouse infected with the polycythemia strain of Friend leukemia virus. The deduced amino acid sequence of a cDNA corresponding to a transcript originating from genomic DNA adjacent to Fli-2 is identical to that of the human heterogeneous nuclear ribonucleoprotein A1 gene, a member of the gene family of RNA-binding proteins involved in RNA splicing. In one erythroleukemia cell line, A1 expression was undetectable as a result of F-MuLV integration in one allele and loss of the other allele. These results suggest that perturbations in RNA splicing mechanisms may contribute to malignant transformation and provide direct evidence that the A1 protein is not required for cell growth.
Mol Cell Biol 1992 Oct
PMID:Retroviral insertions downstream of the heterogeneous nuclear ribonucleoprotein A1 gene in erythroleukemia cells: evidence that A1 is not essential for cell growth. 140 33

The Friend spleen focus-forming virus (SFFV) gp55 glycoprotein binds to the erythropoietin receptor (EPO-R), causing constitutive receptor signaling and the first stage of Friend erythroleukemia. We have used three independent strategies to further define this transforming molecular interaction. First, using a retroviral selection strategy, we have isolated the cDNAs encoding three fusion polypeptides containing regions of both EPO-R and gp55. These fusion proteins, like full-length gp55, transformed the Ba/F3 factor-dependent hematopoietic cell line and localized the transforming activity of gp55 to its transmembrane domain. Second, we have isolated a mutant of gp55 (F-gp55-M1) which binds, but fails to activate, EPO-R. We have compared the transforming activity of this gp55 mutant with the EPO-R-gp55 fusion proteins and with other variants of gp55, including wild-type polycythemia Friend gp55 and Rauscher gp55. All of the fusion polypeptides and mutant gp55 polypeptides were expressed at comparable levels, and all coimmunoprecipitated with wild-type EPO-R, but only the Friend gp55 and the EPO-R-gp55 fusion proteins constitutively activated wild-type EPO-R. Third, we have examined the specificity of the EPO-R-gp55 interaction by comparing the differential activation of murine and human EPO-R by gp55. Wild-type gp55 had a highly specific interaction with murine EPO-R; gp55 bound, but did not activate, human EPO-R.
Mol Cell Biol 1993 Feb
PMID:Fusion of the erythropoietin receptor and the Friend spleen focus-forming virus gp55 glycoprotein transforms a factor-dependent hematopoietic cell line. 842 98

The murine allele temperature-sensitive (ts) p53Val-135 encodes a ts p53 protein that behaves as a mutant polypeptide at 37 degrees C and as a wild-type polypeptide at 32 degrees C. This ts allele was introduced into the p53 nonproducer Friend erythroleukemia cell line DP16-1. The DP16-1 cell line was derived from the spleen cells of a mouse infected with the polycythemia strain of Friend virus, and like other erythroleukemia cell lines transformed by this virus, it grows independently of erythropoietin, likely because of expression of the viral gp55 protein which binds to and activates the erythropoietin receptor. When incubated at 32 degrees C, DP16-1 cells expressing ts p53Val-135 protein, arrested in the G0/G1 phase of the cell cycle, rapidly lost viability and expressed hemoglobin, a marker of erythroid differentiation. Erythropoietin had a striking effect on p53Val-135-expressing cells at 32 degrees C by prolonging their survival and diminishing the extent of hemoglobin production. This response to erythropoietin was not accompanied by down-regulation of viral gp55 protein.
Mol Cell Biol 1993 Mar
PMID:Growth suppression of Friend virus-transformed erythroleukemia cells by p53 protein is accompanied by hemoglobin production and is sensitive to erythropoietin. 844 90

Plethora ('a morbid condition due to excess of red corpuscles') has been recognized since antiquity as a manifestation of disease. The use of leeches and blood letting, which was for centuries the mainstay of therapy in many clinical situations, reflected the importance then attached to having too much blood. Greater knowledge has achieved greater precision, so that measurement of packed cell volume (PCV) or hematocrit now defines polycythemia (> 0.51 in men and > 0.48 in women, when blood is sampled without venous occlusion). Clinical and laboratory investigations, mainly in the last 30 years, have enabled the subdivision of polycythemia into different subtypes of radically different etiology which will be described in this Chapter. The last decade, however, has seen the advancing edge of research in this field passing from clinical and routine laboratory testing to studies of cellular proliferation at the molecular level. Detailed understanding is, however, as always elusive, with each new finding revealing deeper layers which in turn need elucidation. The field of polycythemia is nevertheless moving slowly into the molecular era.
Mol Aspects Med 1996 Apr
PMID:Polycythemia. 881 18

We observed striking differences between the tumorigenic colony-forming cells present in the spleens of mice late after infection with the anemia-inducing strain of Friend leukemia virus (strain FV-A) and those present after infection with the polycythemia-inducing strain (strain FV-P). Cells within primary colonies derived from FV-A- and FV-P-transformed cells (CFU-FV-A and CFU-FV-P, respectively) contained hemoglobin and spectrin, indicating that the CFU-FV-A and CFU-FV-P were transformed erythroid progenitor cells. The proportion of cells containing hemoglobin was relatively high (> 25%) in newly isolated cell lines derived from CFU-FV-P colonies, whereas cell lines derived from CFU-FV-A colonies had only low levels (0 to 2%) of hemoglobin-containing cells. A high proportion of the cell lines derived from CFU-FV-A colonies responded to pure erythropoietin and accumulated spectrin and hemoglobin, whereas the cell lines derived from CFU-FV-P colonies did not. A cytogenetic analysis indicated that primary CFU-FV-P colony cells were diploid, whereas chromosomal aberrations were observed in the immediate progeny of CFU-FV-A. The presence of unique chromosomal markers in the majority of the cells within individual colonies derived from CFU-FV-A suggested that these colonies originated from single cells. Finally, leukemic progenitor cells transformed by strain FV-A appeared to have an extensive capacity to self-renew (i.e., form secondary colonies in methylcellulose), whereas a significant proportion of the corresponding cells transformed by strain FV-P did not. In addition, the self-renewal capacity of both CFU-FV-A and CFU-FV-P increased as the disease progressed. From these observations, we propose a model for the multistage nature of Friend disease; this model involves clonal evolution and expansion from a differentiating population with limited proliferative capacity to a population with a high capacity for self-renewal and proliferation.
Mol Cell Biol 1981 Aug
PMID:Clonal analysis of the late stages of erythroleukemia induced by two distinct strains of Friend leukemia virus. 927 85

In the circulation, fibrinolytic activity is determined to a large degree by the relative levels of tissue plasminogen activator (tPA) and its major inhibitor (PAI-1). Vascular beds in different organs secrete tPA and PAI-1 into the circulation, and the total secretory rate of each protein is balanced by its half-life in the bloodstream. We are testing the hypothesis that in the heart, ventricular hypertrophy will alter the rates of formation of tPA and/or PAI-1 and the rates of their release into the cardiac vasculature. In this study, we have examined the effects of continuous hypoxia on PA activity in extracts of rat heart ventricles, on the activity secreted into the cardiac vasculature of perfused hearts, and on the levels of mRNAs for tPA and PAI-1. Rats were subjected to hypobaric hypoxia at 0.5 atm for 1-21 days. The treatment caused polycythemia within 1-3 days, and right ventricular hypertrophy by 3 days. PA activity in extracts of both right and left ventricles was significantly elevated after 3 days of hypoxia, continued to increase for 4 additional days, and remained elevated for 3 weeks. The actions of inhibitors of urokinase and tPA indicated that the PA activity in heart extracts was exclusively tPA. Fibrin zymography confirmed that result. The mRNAs for tPA and for PAI-1 were elevated after 1 day of hypoxia and then returned to near control levels on days 2 and 3. After 7 days, hearts from hypoxic rats secreted more tPA activity into perfusates than did hearts from controls. The difference in secretory rates was proportional to the differences in the levels of tPA in the corresponding heart extracts.
J Mol Cell Cardiol 1997 Nov
PMID:Secretion of cardiac plasminogen activator during hypoxia-induced right ventricular hypertrophy. 940 84

Female rats develop less severe pulmonary hypertension (PH) in response to chronic hypoxia compared with males, thus implicating a potential role for ovarian hormones in mediating this gender difference. Considering that estrogen upregulates endothelial nitric oxide (NO) synthase (eNOS) in systemic vascular tissue, we hypothesized that estrogen inhibits hypoxic PH by increasing eNOS expression and activity. To test this hypothesis, we examined responses to the endothelium-derived NO-dependent dilator ionomycin and the NO donors S-nitroso-N-acetylpenicillamine and spermine NONOate in U-46619-constricted, isolated, saline-perfused lungs from the following groups: 1) normoxic rats with intact ovaries, 2) chronic hypoxic (CH) rats with intact ovaries, 3) CH ovariectomized rats given 17 beta-estradiol (E(2)beta), and 4) CH ovariectomized rats given vehicle. Additional experiments assessed pulmonary eNOS levels in each group by Western blotting. Our findings indicate that E(2)beta attenuated chronic hypoxia-induced right ventricular hypertrophy, pulmonary arterial remodeling, and polycythemia. Furthermore, although CH augmented vasodilatory responsiveness to ionomycin and increased pulmonary eNOS expression, these responses were not potentiated by E(2)beta. Finally, responses to S-nitroso-N-acetylpenicillamine and spermine NONOate were similarly attenuated in all CH groups compared with normoxic control groups. We conclude that the inhibitory influence of E(2)beta on chronic hypoxia-induced PH is not associated with increased eNOS expression or activity.
Am J Physiol Lung Cell Mol Physiol 2001 Jan
PMID:Estradiol-induced attenuation of pulmonary hypertension is not associated with altered eNOS expression. 1113 98

Chronic hypoxia depolarizes and reduces K+ current in pulmonary arterial smooth muscle cells (PASMCs). Our laboratory previously demonstrated that hypoxia-inducible factor-1 (HIF-1) contributed to the development of hypoxic pulmonary hypertension. In this study, electrophysiological parameters were measured in PASMCs isolated from intrapulmonary arteries of mice with one null allele at the Hif1a locus encoding HIF-1alpha [Hif1a(+/-)] and from their wild-type [Hif1a(+/+)] littermates after 3 wk in air or 10% O2. Hematocrit and right ventricular wall and left ventricle plus septum weights were measured. Capacitance, K+ current, and membrane potential were measured with whole cell patch clamp. Similar to our laboratory's previous results, hypoxia-induced right ventricular hypertrophy and polycythemia were blunted in Hif1a(+/-) mice. Hypoxia increased PASMC capacitance in Hif1a(+/+) mice but not in Hif1a(+/-) mice. Chronic hypoxia depolarized and reduced K+ current density in PASMCs from Hif1a(+/+) mice. In PASMCs from hypoxic Hif1a(+/-) mice, no reduction in K+ current density was observed, and depolarization was significantly blunted. Thus partial deficiency of HIF-1alpha is sufficient to impair hypoxia-induced depolarization, reduction of K+ current density, and PASMC hypertrophy.
Am J Physiol Lung Cell Mol Physiol 2001 Jul
PMID:Partial HIF-1alpha deficiency impairs pulmonary arterial myocyte electrophysiological responses to hypoxia. 1140 63

Chuvash polycythemia (CP) is an autosomal recessive condition that is endemic in the Russian mid-Volga River region of Chuvashia. We previously found that CP patients may have increased serum erythropoietin (EPO) levels, ruled out linkage to both the EPO and EPO receptor (EPOR) gene loci, and hypothesized that the defect may lie in the oxygen homeostasis pathway. We now report a study of five multiplex Chuvash families which confirms that CP is associated with significant elevations of serum EPO levels and rules out a location for the CP gene on chromosome 11 as had been reported by other investigators or a mutation of the HIF-1 alpha gene. Using a genome-wide screen, we localized a region on chromosome 3 with a LOD score >2. After sequencing three candidate genes, we identified a C to T transition at nucleotide 598 (an R200W mutation) in the von Hippel-Lindau (VHL) gene. The VHL protein (pVHL) downregulates the alpha subunit of hypoxia-inducible factor 1 (HIF-1 alpha), the main regulator of hypoxia adaptation, by targeting the protein for degradation. In the simplest scenario, disruption of pVHL function causes a failure to degrade HIF-1 alpha resulting in accumulation of HIF-1 alpha, upregulation of downstream target genes such as EPO, and the clinical manifestation of polycythemia. These findings strongly suggest that CP is a congenital disorder of oxygen homeostasis.
Blood Cells Mol Dis
PMID:Endemic polycythemia in Russia: mutation in the VHL gene. 1198 42

In vivo gene transfer is being considered in the systemic delivery of therapeutic proteins. This report evaluates the use of AAV vectors administered into muscle to deliver erythropoietin (Epo) for the treatment of anemia in a mouse model of beta-thalassemia. Injection of vector expressing Epo from a constitutive promoter resulted in Epo overproduction and improved erythropoiesis. However, severe and lethal polycythemia developed. In order to titrate the expression of Epo to therapeutic and non-toxic levels, vectors were constructed to allow pharmacologic control of Epo transcription. Specifically, expression of Epo was dependent on the presence of a chimeric transcription factor that is activated by the orally available small molecule drug rapamycin. beta-thalassemic mice injected with vectors containing the regulated Epo gene failed to show any effect until they were administered a regimen of rapamycin, which led to the production of Epo and an increase in hematocrit values. Epo expression and its hematologic consequences were directly dependent on the dose of rapamycin and were completely reversed when rapamycin was withdrawn. The increase in hematocrit was associated with partial improvements in the abnormalities of red blood cell morphology. This study confirms the value of pharmacologic regulation of transgene expression in the development of safe and effective gene therapies in which biologically active secreted proteins are produced.
Mol Ther 2003 Apr
PMID:Regulated expression of erythropoietin from an AAV vector safely improves the anemia of beta-thalassemia in a mouse model. 1272 12


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