RNA Tumor Viruses Research Articles

ADP-ribosylation of chromosomal proteins and mouse mammary tumor virus gene expression. Glucocorticoids rapidly decrease endogenous ADP-ribosylation of nonhistone high mobility group 14 and 17 proteins.

The relationship between endogenous ADP-ribosylation of chromosomal proteins and glucocorticoid-regulated mouse mammary tumor virus gene expression was investigated in cultured mouse mammary tumor cells. It was observed that glucocorticoids quickly decreased endogenous (ADP-ribose)n on the nonhistone high mobility group (HMG) 14 and 17 proteins. The half-time for this loss was 8 and 17 min, respectively, for the two proteins. (ADP-ribose)n on HMG 1 and 2 and on histone H1 was less susceptible to hydrolysis during glucocorticoid treatment. The rapid loss of (ADP-ribose)n from HMG 14 and 17 occurred in the same time frame as the induction of mouse mammary tumor virus RNA synthesis by glucocorticoids in these cells (Young, H. A., Shih, T. Y., Scolnick, E. M., and Parks, W. P. (1977) J. Virol. 21, 139-149). 3-Amino-benzamide, a specific inhibitor of (ADP-ribose)n synthetase, increased mouse mammary tumor virus RNA levels with an accompanying decrease in endogenous ADP-ribosylation of HMG 14 and 17. These results show that a decrease in endogenous ADP-ribosylation of HMG 14 and 17 is a consequence of glucocorticoid action and suggest that loss of (ADP-ribose)n from these proteins may be an important event in mouse mammary tumor virus gene expression.

Sequence homology between retroviral reverse transcriptase and putative polymerases of hepatitis B virus and cauliflower mosaic virus.

In infected cells, the RNA genomes of RNA tumour viruses are copied into DNA by a virus-encoded reverse transcriptase enzyme. This transfer of information from RNA into DNA was thought to be a unique feature of RNA tumour viruses, but recent results suggest it may be a more general strategy. Hepatitis B virus (HBV) has a double-stranded DNA genome, and it has recently been shown that the minus DNA strand of the HBV genome is copied from a plus-strand RNA template, leading to the suggestion that reverse transcription is central to the life cycle of HBV. More recently it has been suggested that the replication cycle of a plant virus, cauliflower mosaic virus (CaMV), includes a reverse transcription step. We report here the existence of amino acid sequence homology between retroviral reverse transcriptase and the putative polymerases of HBV and CaMV.

RNA tumor virus production accompanies the transformed phenotype change induced by hydrocortisone hormone in rat glioma cells

ST1, a hydrocortisone-hypersensitive variant of the C 6 rat glioma cell line, produced viral particles upon treatment with this glucocorticoid hormone. The virus was identified as type C RNA tumor virus by: a) morphology; b) 3H-uridine labelling; c) banding in sucrose density gradient; d) reverse transcriptase activity. Hydrocortisone uniquely shut off ST1 cells' transformed phenotype and turned on viral particles production.

Induction of the acute-phase reactant, alpha 1-acid glycoprotein, by glucocorticoids in rat hepatoma cells.

alpha 1-acid glycoprotein (alpha 1-AGP), or orosomucoid, is shown to be inducible by glucocorticoids in HTC rat hepatoma cells. Immunoprecipitation of [35S]methionine pulse-labeled proteins from these cells reveals secreted proteins of Mr = 35,000-48,000 (alpha 1-AGP) and Mr greater than 180,000, both of which are greatly enhanced by glucocorticoid treatment. The amount of alpha 1-AGP-specific mRNA in HTC cells is greatly increased (at least 100-fold) in response to glucocorticoids. The new steady-state level of RNA is approached with a t 1/2 of about 8 hr and the RNA consists of a single species of approximately 850 bases. The response is specific for glucocorticoids since: (i) the EC50 for dexamethasone is 30 nM; (ii) the glucocorticoid antagonist, progesterone, inhibits the induction by dexamethasone; and (iii) a glucocorticoid receptor-deficient cell line is incapable of alpha 1-AGP mRNA induction. This is a secondary hormonal response since inhibition of protein synthesis blocks the induction of alpha 1-AGP mRNA by dexamethasone whereas the induction of mouse mammary tumor virus (MMTV) RNA is unaffected.

Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour.

Amplified cellular genes in mammalian cells frequently manifest themselves as double minute chromosomes (DMs) and homogeneously staining regions of chromosomes (HSRs). With few exceptions both karyotypic abnormalities appear to be confined to tumour cells. All vertebrates possess a set of cellular genes homologous to the transforming genes of RNA tumour viruses, and there is circumstantial evidence that these cellular oncogenes are involved in tumorigenesis. We have recently shown that DMs and HSRs in cells of the mouse adrenocortical tumour Y1 and an HSR in the human colon carcinoma COLO320 contain amplified copies of the cellular oncogenes c-Ki-ras and c-myc, respectively. Both DMs and HSRs are found with remarkable frequency in cells of human neuroblastomas. We show here that a DNA domain detectable by partial homology to the myc oncogene is amplified up to 140-fold in cell lines derived from different human neuroblastomas and in a neuroblastoma tumour, but not in other tumour cells showing cytological evidence for gene amplification. By in situ hybridization we found that HSRs are the chromosomal sites of the amplified DNA. The frequency with which this amplification appears in cells from neuroblastomas and its apparent specificity raise the possibility that one or more of the genes contained within the amplified domain contribute to tumorigenesis.

Human T-Cell Leukemia-Lymphoma Virus and Adult T-Cell Leukemia

THE ISOLATION and characterization of the human T-cell leukemia-lymphoma virus (HTLV)^1-5and its relationship to adult T-cell leukemia (ATL)^6-8represent the remarkable convergence of scientific discoveries made half a world apart. The discovery of HTLV represents the culmination of a search for a true human retrovirus (type C virus) that dates back more than 50 years. Almost simultaneous to this breakthrough was the remarkable recognition of a distinctive clinicopathologic entity, ATL.^9-11The molecular and clinical studies summarized in this review represent a scientific tale of two cities, Bethesda, Md, and Kyoto, Japan. <h3>HTLV: A Prototype Human Retrovirus</h3> In numerous animal species, naturally occurring leukemias or lymphomas are caused by retroviruses (also known as type C viruses, RNA tumor viruses, leukemia viruses).^12-14This class of virus is characterized by a replication cycle requiring integration of the viral genetic material in the form of a provirus into host

The Human T-Cell Leukemia-Lymphoma Virus in the Southeastern United States

The human T-cell leukemia-lymphoma virus (HTLV) is a recently described RNA tumor virus associated with human T-cell malignant neoplasms. In two geographic areas, Japan and the Caribbean basin, clusters of adult T-cell leukemia-lymphoma are "sentinel diseases" and have suggested an underlying prevalence of HTLV infection in both family members of the index cases and in the population. Four cases of lymphoma from the United States are described as illustrative of the sentinel disease. Serological studies of families and of a small population sample suggest that HTLV infection is endemic in certain parts of the southeastern United States at rates similar to those seen in Caribbean blacks but at a lower rate than that observed in southwestern Japan.

Avian sarcoma viruses, protein kinases and cell transformation.

The first RNA tumour virus to be isolated and identified as such was the Rous sarcoma virus (RSV), which causes the transformation of cells in culture as well as fibrosarcomas when injected into suitable host animals (for reviews see Hanafusa (1977) and Bishop (1978)). The genome of RSV has been studied intensively for the past 10-12 years, and it has been shown that the virus itself carries a gene responsible for malignant transformation. This gene, denotedsrcfor sarcoma, was identified genetically through the isolation of temperature-sensitive mutants that were conditional for cell transformation in culture. These mutants are able to transform cells at a temperature of 35 °C, the permissive temperature, but are unable to transform cells morphologically at 41 °C, the non-permissive temperature. The existence of such temperature sensitive mutants implied that the product of the viral transforming gene, in RSV, was a protein (Kawai &amp; Hanafusa 1971). In addition to temperature-sensitive mutants, non-conditional mutants were isolated that had deletions of the src gene. These mutants are unable to transform cells in culture or to cause fibrosarcomas under most conditions. About 4 years ago, the product of the src gene was identified as a phosphoprotein (Mt= 60000); this protein was denoted pp60src(Purchioet al.1978). The RSV genome and the expression of the src gene is illustrated in figure 1.

Myeloproliferative sarcoma virus: its effects on erythropoiesis in adult DBA/2J mice.

Adult susceptible mice (DBA/2J) infected with MPSV (myeloproliferative sarcoma virus), a defective RNA tumour virus, develop splenomegaly and progressive disruption of the haematologic system culminating in death. The present study was specifically directed toward determining the effects of the virus on erythroid differentiation. Early and late precursor cells (erythroid burst-forming units; BFU-E and colony-forming units; CFU-E, respectively) were evaluated by the ability of bone marrow and spleen cells to form colonies of fully differentiated erythroid cells in vitro. MPSV caused substantial modification of both the BFU-E and CFU-E populations in the bone marrow and spleen of infected animals. Changes were detected in the CFU-E population preceding any significant increase in spleen weight. In the bone marrow, the proportion of CFU-E cells increased almost twofold by days 5-10 after virus infection but decreased by day 15. In the spleen, CFU-E frequency rose 40-fold by days 10-15 and then declined steadily prior to death. At the peak of CFU-E expansion, a small proportion of the population appeared to be erythropoietin (Ep) independent, although there was no evidence of a complete switch to Ep-independence which occurs in Friend virus-induced erythroleukemia. Dose-response curves showed that none of these data could be explained in terms of a changing responsiveness to Ep. However, evidence is presented that indicates that BFU-E from MPSV-infected animals lose or have a reduced requirement for burst-promoting activity (BPA) relative to normal cells although their progeny still need Ep for terminal erythroid differentiation.

Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS).

A retrovirus belonging to the family of recently discovered human T-cell leukemia viruses (HTLV), but clearly distinct from each previous isolate, has been isolated from a Caucasian patient with signs and symptoms that often precede the acquired immune deficiency syndrome (AIDS). This virus is a typical type-C RNA tumor virus, buds from the cell membrane, prefers magnesium for reverse transcriptase activity, and has an internal antigen (p25) similar to HTLV p24. Antibodies from serum of this patient react with proteins from viruses of the HTLV-I subgroup, but type-specific antisera to HTLV-I do not precipitate proteins of the new isolate. The virus from this patient has been transmitted into cord blood lymphocytes, and the virus produced by these cells is similar to the original isolate. From these studies it is concluded that this virus as well as the previous HTLV isolates belong to a general family of T-lymphotropic retroviruses that are horizontally transmitted in humans and may be involved in several pathological syndromes, including AIDS.

Enzyme Inhibition VI: Inhibition of Reverse Transcriptase Activity by Protoberberine Alkaloids and Structure–Activity Relationships

□ Protoberberine alkaloids such as palmatine (I), 13-meth- ylpalmatine iodide (II), 2,3-methylenedioxy-10,ll-dimethoxy-13- methylprotoberberine iodide (III), 2,3-methylenedioxy-9,10-dime- thoxy-13-methylprotoberberine chloride (IV), and berberine (V) showed inhibition of reverse transcriptase activity of RNA tumor viruses in the presence of polyriboadenylic acid-oligodeoxythymidylic acid (VI), polydeoxyadenylic acid-oligodeoxythymidylic acid (VII), activated calf thymus deoxyribonucleic acid (IX), and 70S ribonucleic acid (X), but not in the presence of polyribocytidylic acid-oligodeoxyguanylic acid (VIII). These results indicated that the alkaloids caused inhibition of the enzyme activity by interacting with the template primer, particularly of the adenine-thymine base pair. Furthermore, the alkaloids competed with the template primer-binding site of the enzyme. The time course inhibition indicated that the alkaloids stopped the DNA synthesis instantly when added after the initiation of polymerization processes. Inhibition of reverse transcriptase activity was correlated with the structure and antileukemic activity of the protoberberine alkaloids.

Region-specific initiation of mouse mammary tumor virus RNA synthesis by endogenous RNA polymerase II in preparations of cell nuclei.

Adenosine 5'-O-(2-thiotriphosphate) (ATP beta S) and guanosine 5'-O-(2-thiotriphosphate) (GTP beta S) were used to demonstrate initiation of mouse mammary tumor virus (MMTV) RNA in preparations of whole nuclei from control and glucocorticoid-treated MMTV-infected rat hepatoma tissue culture cells. RNA chains initiated in the cell-free reaction retain a thiol group at the 5' end and can be separated from thiol-free RNA chains by chromatography on mercury-Sepharose. The abundance of MMTV sequences was determined by nucleic acid hybridization with filter-bound DNA representing four different regions of the MMTV genome. About six times more MMTV RNA is initiated with GTP beta S than with ATP beta S. Most of the cell-free initiation of MMTV RNA occurs within or very near a 380-nucleotide section of the proviral long terminal repeat that is the presumptive site of transcription initiation in vivo. The sensitivity of MMTV RNA initiation and synthesis to alpha-amanitin and actinomycin D are characteristic of DNA-directed transcription by RNA polymerase II. Nuclei from glucocorticoid-treated cells initiate approximately 10 times more MMTV RNA than nuclei from control cells.

Mechanism of action of the endonuclease associated with the alpha beta and beta beta forms of avian RNA tumor virus reverse transcriptase.

Preparations of the alphabeta and the betabeta forms of reverse transcriptase from the Prague C strain of Rous sarcoma virus grown in chicken embryo fibroblasts, the alphabeta and the betabeta forms of the enzyme from the B77 strain of Rous sarcoma virus grown in duck embryo fibroblasts, and the alphabeta form of reverse transcriptase from avian myeloblastosis virus have been analyzed. All these enzyme preparations contain a Mn(2+) -activated endonuclease activity. The betabeta form of enzyme, in addition, contains a Mg(2+) -dependent endonuclease. Such an activity is barely detectable in the alphabeta form of enzymes. The endonuclease associated with reverse transcriptase introduces single- and double-strand breaks containing 3' OH and 5' P termini into RF I DNA. The conversion of RF I DNA to RF III DNA is more readily catalyzed by the betabeta form of reverse transcriptase. In contrast to a recently published report by Hizi et al. (J. Virol 41:974-981, 1982), we have failed to detect the conversion of RF I DNA to covalently closed relaxed circles (RF IV DNA) by any of the alphabeta form of enzymes tested. RF IV DNA was not produced by the betabeta form of reverse transcriptase either. We conclude that topoisomerization is not an intrinsic activity of reverse transcriptase. Although the conversion of RF I DNA to RF II DNA was found to be rapid, the endonuclease associated with reverse transcriptase acted slowly on RF II, RF III, and RF IV DNAs. Circular and linear single-stranded DNAs were also susceptible to cleavage by the endonuclease at a rate comparable to nicking of RF I DNA. This pattern of activity suggests that the endonuclease cleaves the RF I DNA in the single-stranded regions of the DNA induced by its supercoiling. The preference of the alphabeta and the betabeta forms of the endonuclease for viral DNA was tested with Rous-associated virus type 2 and Rous sarcoma virus transformation-defective Schmidt-Ruppin B strain DNA molecularly cloned in plasmid pBR322 and M13 DNA vectors, respectively. The rate of nicking of RF I DNA containing viral DNA or partial sequences of viral DNA with one or two tandem long terminal repeats was the same as when these sequences were not present in the host vectors. A similar lack of preference was observed with single-stranded M13 DNAs.

RNA tumor viruses: Cancer's fifth column. “RNA Tumor Viruses. The Molecular Biology of Tumor Viruses,” Robin Weiss, Natalie Teich, Harold Varmus, and John Coffin (eds). Cold Spring Harbor, New York: Cold Spring Harbor Laboratory, Second Edition, 1982, 1396 pp, $125.00

Environmental MutagenesisVolume 5, Issue 4 p. 637-640 Book Reviews RNA tumor viruses: Cancer's fifth column. “RNA Tumor Viruses. The Molecular Biology of Tumor Viruses,” Robin Weiss, Natalie Teich, Harold Varmus, and John Coffin (eds). Cold Spring Harbor, New York: Cold Spring Harbor Laboratory, Second Edition, 1982, 1396 pp, $125.00 John Delehanty, John Delehanty National Academy of Sciences, Washington, D.CSearch for more papers by this author John Delehanty, John Delehanty National Academy of Sciences, Washington, D.CSearch for more papers by this author First published: 1983 https://doi.org/10.1002/em.2860050412AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume5, Issue41983Pages 637-640 RelatedInformation

Naturally occurring retroviruses (RNA tumor viruses). I.

This is the first of two papers describing the naturally occurring retroviruses (RNA tumor viruses). Here, the general properties of these viruses and the biology of the fish, reptilian, chicken, and mouse retroviruses are described. In the next issue of Cancer Investigation the biologic properties of the cat, cattle, primate, and newly discovered human retroviruses will be discussed.

Naturally occurring retroviruses (RNA tumor viruses). II (Continued).

This is Part two of this paper describing the biology of the naturally occurring RNA tumor viruses (oncornaviruses) in “higher” vertebrates. Part one [Cancer Investigation 1(2):163-174, 1983] discussed cat retroviruses. Part two deals with bovine and primate, including human, RNA tumor viruses. A. review of retroviruses in “lower” animals preceded this paper

Naturally occurring retroviruses (RNA tumor viruses). II.

This is the second of two papers describing the biology of the naturally occurring RNA tumor viruses (oncoviruses). It will appear in two parts. In the first paper [Cancer Investigation 1(1):67-83 (1983)] the general properties of this class of viruses and the biology of the retroviruses of the "lower" vertebrates was discussed. In this paper the oncoviruses of the "higher" animals are described. Part one deals with cat retroviruses.

Regulation of Cell Proliferation by Epidermal Growth Factor

Epidermal Growth Factor (EGF) is a 6045 dalton polypeptide which stimulates the proliferation of various cell types in vitro and in vivo. EGF binds to diffusely distributed membrane receptors which rapidly cluster primarily on coated pits areas on the plasma membrane. Subsequently, the EGF-receptor complexes are endocytosed and degraded by lysosomal enzymes. The lateral diffusion coefficient (D) of EGF-receptor complexes on cultured cells increases gradually from D = 2.8 X 10(-10) cm2/sec at 5 degrees C to 8.5 X 10(-10) cm2/sec at 37 degrees C. In the same range of temperature the rotational correlation times change from 25 to 50 microseconds to approximately 350 microseconds. Hence, at 4 degrees C, the occupied EGF receptors translate and rotate rapidly in the plane of the membrane. At 37 degrees C, EGF receptors form microclusters composed of 10 to 50 molecules. Moreover, it is concluded that both at 4 degrees C and 37 degrees C lateral diffusion of the occupied receptors is not the rate determining step for either receptor clustering or internalization. EGF receptor is a 150,000 to 170,000 dalton glycoprotein. The receptor is in close proximity to an EGF-sensitive, cAMP-independent, tyrosine-specific protein kinase which also phosphorylates the receptor molecules itself. The EGF sensitive kinase is similar to the kinase activity which is associated with certain RNA tumor viruses. The fact that the non-mitogenic cyanogen-bromide cleaved EGF is as potent as native EGF in stimulating phosphorylation suggests that EGF-induced, protein phosphorylation is a necessary but insufficient signal for the induction of DNA synthesis by EGF. EGF receptor serves also as the binding site for Transforming Growth Factors (TGF) which compete with EGF and induce anchorage-independent growth of normal cells in soft agar. Tumor promoters such as phorbol ester effect the binding of EGF to its membrane receptors and its ability to stimulate DNA synthesis. EGF itself has also some tumor promoting activity. Hence, the membrane receptor for EGF seems to participate in the regulation of normal and neoplastic growth. Monoclonal antibodies against EGF receptor (IgM) induce various early and delayed effects of EGF, while their monovalent Fab' fragments are devoid of biological activity. These observations support the notions that EGF receptor rather than EGF itself is the active moiety and that the role of the hormone is to perturb the receptor in the appropriate way, probably by inducing the microaggregation of EGF receptors.

Epidemiology of HTLV-associated leukemia.

Type-C retroviruses have long been implicated in the etiology of leukemia and lymphoma in various animal species. Animal models exist for exogenous, horizontal, transmission of these naturally occurring RNA tumor viruses in animals and are especially well characterized for cat, cow, and some other species [21]. Human T-cell leukemia- lymphoma virus (HTLV) is the first type-C retrovirus consistently isolated and associated with specific human malignancies. It is distinct from previously identified animal retroviruses by molecular [15] and immunologic studies [10, 16, 17]. It is an exogenous virus that must be acquired by infection (i.e., not transmitted in the germ line), since HTLV proviral sequences are present in DNA of neoplastic T cells, but not in DNA of nonneoplastic B cells from the same patient [7] or in normal tissues [15].KeywordsHairy Cell LeukemiaDiffuse Large Cell TypeKalyanaraman VersusVirus Antibody PositiveThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Detection of group and interspecies reactivities in mammalian C-type virus p30 proteins and corresponding human antigens.

We previously reported the presence of RNA tumor virus related antigens in human leukemic sera. The antigens were detected by the ELISA method in 30%–40% of patients with acute leukemia [1, 2]. Since these antigens from human sera that cross-react with primate C-type viral p30 protein had been observed with the ELISA method and since retroviral group and interspecies reactivities had been previously characterized mostly by competition radioimmunoassay, we examined the applicability and reliability of the ELISA method for the detection of group and interspecific determinants in p30 proteins of mammalian C-type retroviruses [4].KeywordsELISA MethodHuman SeronHuman AntigenHomologous AntigenCompetition ELISAThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.