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Presence and Expression of Friend Erythroleukemia Virus-Related Sequences in Normal and Leukemic Mouse Tissues

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Presence and Expression of Friend Erythroleukemia Virus-Related Sequences in Normal and Leukemic Mouse Tissues Proc. Natl. Acad. Sci. USA Vol. 76, No. 9, pp. 4455-4459, September 1979 Cell Biology Presence and expression of Friend erythroleukemia virus-related sequences in normal and leukemic mouse tissues (RNA tumor viruses/Friend spleen focus-forming virus/mechanism of transformation/differentiation/gene expression) ALAN BERNSTEIN, CATHERINE GAMBLE, DONNA PENROSE, AND TAK W. MAK The Ontario Cancer Institute, and Department of Medical Biophysics, University of Toronto, 500 Sherbourne Street, Toronto, Ontario, Canada M4X 1K9 Communicated by J. Tuzo Wilson, May 22, 1979 ABSTRACT The nature and distribution of sequences re- Although the origin and nature of sarcoma virus-specific lated to the murine erythroleukemia virus, Friend spleen sequences have been well characterized, no comparable studies focus-forming virus (SFFV), have been analyzed by using a ra- have been reported on the rapidly transforming mammalian dioactive cDNA probe specific for the SFFV genome (cDNAsff). From the proportion of high molecular weight viral [32PJRNA leukemia viruses. These viruses, which include the murine which hybridized to cDNAsff, it was estimated that these se- Abelson (9) and Friend (10-12) leukemia viruses, are replica- quences represent about 50% of the SFFV genome, indicating tion-defective and hence require helper virus to produce in- a genetic complexity of about 3300 nucleotides. cDNAff hy- fectious progeny. Immunological and molecular hybridization bridized extensively (80-95%) to SFFV virion RNA and to cel- analyses of cell clones nonproductively infected with the de- lular RNA from murine and rat cells productively or nonpro- fective Friend focus- ductively infected with SFFV. Only background homology was erythroleukemia-inducing virus, spleen detected between cDNAff and viral RNA from a number of forming virus (SFFV), have indicated that the SFFV genome murine [Friend murine leukemia virus (MuLV), Moloney-MuLV, contains some, but not all, of the sequences found on its helper and Kirsten sarcoma virus] and nonmurine (Rous sarcoma virus, lymphoid leukemia virus (13, 14). In addition, the SFFV ge- feline leukemia virus, baboon endogenous virus, and Mason- nome, like rapidly transforming sarcoma viruses, contains Pfizer mammary tumor virus) retroviruses. Limited homology unique sequences that are not found on its helper lymphoid was also detected to a number of murine xenotropic and mink leukemia virus The that these cell focus-inducing viruses (20-35%) as well as Rauscher leu- (13-16). possibility SFFV-specific kemia virus (50%). Nucleotide sequences homologous to sequences code for a functional polypeptide is suggested by the cDNAsff were also detected in the DNA of normal cells of sev- observations that SFFV nonproducer cells express a high mo- eral mouse strains as single or a few copies per cell. Thermal lecular weight polyprotein that contains both virion structural denaturation analysis indicated that duplexes formed between and nonstructural components (17) and that the infection of cDNAsff and normal DBA/2J cellular DNA have a reduction in homologous or heterologous cells with SFFV results in the ap- melting temperature of 2VC when compared with the disso- of a new cell surface that is not found on ciation of hybrids between cDNAsff and homologous sequences pearance antigen in SFFV-infected mouse spleen cell DNA. Examination of cel- helper virus-infected cells (18). lular RNA from uninfected mouse cells indicated that SFFV- In this study, we have used a single-stranded DNA probe related RNA sequences were also expressed in varying degrees complementary to a portion of the replication-defective SFFV in different tissues of adult DBA/2J mice. The highest amounts genome that is not shared with its helper virus (cDNAff) (15) were observed in cells from bone marrow and spleen, whereas to demonstrate that nucleotide sequences that are highly related considerably lower amounts were found in cells from the thy- mus and kidney. No SFFV-related sequences could be detected to these SFFV-specific sequences are present in normal mouse in RNA extracted from liver, muscle, or fibroblasts. The presence cellular DNA. Furthermore, these cellular SFFV-related se- of these SFFV-related sequences in normal, uninfected mouse quences appear to be differentially expressed into RNA in cells cell DNA and their differential expression in hematopoietic from hematopoietic tissues of adult mice. tissues suggest that these sequences may be an integral part of the program of both normal and leukemic hematopoietic cell MATERIALS AND METHODS differentiation. Cells and Viruses. Cells were grown in alpha medium (19) Molecular analysis of the genomes of a number of avian and supplemented with 10% fetal bovine serum. Cell lines included murine sarcoma viruses has advanced considerably our un- NIH/3T3 and NRK cells nonproductively infected with SFFV, derstanding of viral carcinogenesis. Such studies have indicated NIH/3T3 cells productively infected with both the polycyth- that the genomes of these viruses contain unique sequences that emic strain of SFFV and its NB-tropic helper Friend murine have either been implicated or shown to be involved in the rapid leukemia virus (F-MuLV), and NIH/3T3 cells productively malignant transformation of fibroblasts (1-3). The observation infected with the cloned helper F-MuLV. These cell lines have that nucleotide sequences highly related to these sarcoma all been described (13). A fetal lung mink cell line CCL64 was virus-specific sequences (src) have been found in the DNA of obtained from J. Stephenson (National Institutes of Health, normal avian (4) and murine (5) cells has led to the hypothesis Bethesda, MD 20205). SFFV and its helper F-MuLV were that these rapidly transforming viruses may have arisen as the harvested from the above NIH/3T3 cell lines. Xenotropic result of a recombination event between a type C leukemia murine type C viruses, including BALB/virus-2 [BALB/c- virus and host src sequences. In addition, sequences related to murine xenotropic virus (XLV)], NZB-XLV, and a mink cell the src gene of Rous sarcoma virus appear to be transcribed (6) focus-inducing virus isolated from AKR mice (MCF-274) were and translated (7, 8) in normal chicken embryo fibroblasts, al- a role for these sequences in normal cell functon has not Abbreviations: SFFV, Friend spleen focus-forming virus; F-MuLV, though Friend murine leukemia virus; XLV, murine xenotropic virus; MCF, yet been determined. mink cell focus-inducing virus; cDNAsff, purified single-stranded DNA complementary to specific sequences on the SFFV genome; Crt, initial The publication costs of this article were defrayed in part by page concentration of RNA in moles of nucleotide per liter X time in sec- charge payment. This article must therefore be hereby marked "ad- onds; Cot, initial concentration of DNA in moles of nucleotide per liter vertisement" in accordance with 18 U. S. C. §1734 solely to indicate X time in seconds; Cot112, Cot necessary for 50% hybridization; Crtl/2, this fact. Crt necessary for 50% hybridization. 4455 Downloaded by guest on September 24, 2021 4456 Cell Biology: Bernstein et al. Proc. Natl. Acad. Sci. USA 76 (1979) obtained from J. Hartley (National Institutes of Health). These after incubation, the tubes were broken and the extent of hy- xenotropic viruses were propagated on CCL64 cells by using bridization was determined by hydrolysis with the single- described procedures (13). Moloney leukemia virus and strand-specific nuclease, S1. Rauscher leukemia virus were obtained from A. Wu (Depart- DNA-cDNA Hybridization. DNA was extracted from tissue ment of Anatomy, University of Toronto, Toronto, Canada). by a described method (22). For hybridization, cellular DNA Kirsten sarcoma virus, Rous sarcoma virus, feline leukemia sonicated to 6 S20,w was mixed with about 1000 cpm of cDNA virus, baboon endogenous virus, and Mason-Pfizer mammary in a mixture containing 0.75 M NaCl, 10 mM EDTA, 25 mM virus were all obtained from J. Gruber (National Cancer In- Tris-HCl (pH 7.4), and 50% formamide (crystallized five times). stitute). The reaction mixture containing about 15 mg of DNA per ml Mice. All mice used in these experiments were purchased was incubated at 400C. At various times the sealed glass tubes from the Jackson Laboratory. were broken and the SI-nuclease-resistant counts were deter- Preparation of High Molecular Weight Viral [32P]RNA. mined. NIH-3T3 cells chronically infected with SFFV (F-MuLV) were Thermal Denaturation Analysis. Hybrids between cellular used to prepare viral [32P]RNA. These cultures released virus DNA and viral cDNA were formed as described above [final stocks containing a SFFV-to-F-MuLV ratio of approximately Cot of >20,000 (mol/liter) X sec]. After hybridization, the re- 10:1 (15). The chronically infected NIH-3T3 cells were incu- action mixture was diluted 200-fold into 0.14 M sodium phos- bated in phosphate-free a-medium containing 10% dialyzed phate buffer (pH 7.4). The mixture was then loaded into a fetal calf serum and 2 mCi of 32P-phosphate (Amersham Searle) hydroxylapatite column and a temperature gradient ranging per ml for 18 hr (1 Ci = 3.7 X 1010 becquerels). The medium from 50°C to 95°C in 5°C intervals of prewarmed 0.14 M was then replaced with phosphate-free medium without iso- phosphate buffer plus 0.4% sodium dodecyl sulfate was used tope. The medium was harvested at intervals of 2 hr and virus to elute single-stranded DNA. Fractions (5 ml) were collected was purified by centrifugation through a 20-60% sucrose gra- and analyzed for acid-insoluble radioactivity. dient as described (13, 15). The 32P-labeled virus, which banded at densities of 1.14-1.16 gm/ml, was then pelleted at 100,000 RESULTS X g for 2 hr and resuspended in TNE (0.02 M Tris-HCl, pH Genetic Complexity of the Nucleotide Sequences in 7.4/0.14 M NaCI/10 mM EDTA) containing 1% sodium do- cDNAsff.
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