Integration and transcription of mouse mammary tumor virus DNA in rat hepatoma cells.

Ringold, Gordon M.; Shank, Peter R.; Varmus, Harold; Ring, Janet

doi:10.1073/pnas.76.2.665

Cited by 110 publications

(51 citation statements)

References 27 publications

(28 reference statements)

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“…MMTV infects mammary epithelial cells and randomly inserts its proviral DNA into the host somatic cell DNA during its replicative cycle (Ringold et al, 1979;Withers-Ward et al, 1994). As discussed below some of these random insertions have been shown to cause deregulation of cellular (INT) genes leading to premalignant transformation and subsequently to tumor progression.…”

Section: The Mmtv Infectious Pathwaymentioning

confidence: 99%

MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways

2000

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The study of the mouse mammary tumor virus (MMTV) has provided important insights into the mechanisms of gene transcription regulation by steroid hormones, the mode of action of heritable super antigens and the progressive nature of neoplastic transformation in the mammary gland. Here we describe the current situation with respect to the latter aspect of MMTV biology and the prospects for further advance in our understanding of breast cancer in humans that may be expected from a continued study of MMTV-induced mammary neoplasia. MMTV is a heritable somatic mutagen whose target range is limited. Commonly, the tumorigenic capacity of MMTV is restricted to mammary gland, whereas infection is found in a variety of cell types. In order to replicate, proviral DNA must be inserted into the cell DNA and cell division is required to ®x the mutation. Yet only in the mammary epithelium does this lead to neoplastic transformation. This suggests a unique relationship between MMTV and mammary epithelium. In evaluating this relationship, we and others have discovered genes and potential gene pathways that are pertinent in mammary di erentiation and neoplasia. In addition, the clonal nature of these progressive events from normal to malignant phenotype has become increasingly clear. The weight of these observations compel us to conclude that mammary neoplasms arise from multipotent mammary epithelial cells through a process of acquired mutations that are re¯ected in the increasingly malignant nature of the population of progeny produced by these damaged stem cells.

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Section: The Mmtv Infectious Pathwaymentioning

confidence: 99%

MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways

2000

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“…This report describes a genetic approach to the analysis of glucocorticoid action with M1.54, a cloned line of infected cultured rat hepatoma (HTC) cells containing 10 stably integrated MTV proviruses per cellular genome (30,47 (30,47); the viral genes have no apparent effect on growth and viability of M1.54, and no MTV virions are produced. Cells were grown in monolayer culture in Dulbecco modified Eagle medium or in suspension in Swim 77 medium (GIBCO), each supplemented with 5% horse serum; cultures were maintained at 37°C in a humid atmosphere of air-CO2 cells per 100-mm dish), propagated for 24 h in medium containing heat-inactivated horse serum and 1 ,uM dexamethasone, were exposed for an additional 24 h to 4 ml of the same medium containing 10 ,ul of rabbit anti-MTV serum and 0.4 ml of rabbit complement per dish.…”

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confidence: 99%

Two classes of mutant mammary tumor virus-infected HTC cell with defects in glucocorticoid-regulated gene expression.

Firestone¹,

Yamamoto²

1983

Mol. Cell. Biol.

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We have isolated mutant derivatives of M1.54 (a mammary tumor virus [MTV]infected rat hepatoma [HTC] cell line containing multiple integrated proviruses) that fail to express hormone-inducible cell surface viral glycoproteins. In wildtype M1.54, the synthetic glucocorticoid dexamethasone selectively stimulates the rate of synthesis of MTV RNA. In addition, dexamethasone is essential for posttranslational maturation of three of the four cell surface viral glycoproteins processed from the MTV glycosylated precursor polyprotein; the fourth mature species is produced constitutively. Two mutant phenotypes are described; each contains glucocorticoid receptors that are indistinguishable from the wild-type receptor with respect to hormone affinity, intracellular concentration, nuclear translocation efficiency, DNA-cellulose chromatography, and sedimentation rate. In one class, represented by the mutant line CR1, dexamethasone fails to stimulate the low basal rate of MTV gene transcription; surprisingly, hormonal regulation of tyrosine aminotransferase activity is also defective in CR1, whereas several other cellular responses to dexamethasone are normal. In the second class of mutants, represented by CR4, dexamethasone stimulates synthesis of MTV transcripts indistinguishable from those produced in M1.54, but only the constitutive cell surface viral glycoprotein is expressed. Thus, these mutants define two distinct and novel aspects of glucocorticoid regulated gene expression in HTC cells: CR4 contains a defect in a hormone inducible protein maturation pathway that acts on specific viral (and presumably cellular) precursor polypeptides, whereas the lesion in CR1 appears to affect the expression of a subset of the gene products normally under glucocorticoid control in M1.54.Among vertebrates, glucocorticoid hormones affect the expression of specific genes in virtually every tissue; interestingly, the set of gene products whose synthesis or activities are altered, i.e., the glucocorticoid domain (16), is highly cell type specific (2). The effects of glucocorticoids and other steroids appear to be mediated by hormone-specific intracellular receptor proteins; the hormone-receptor interaction potentiates a change in the receptor (activation) that results in its increased affinity for DNAcontaining sites in the cell nucleus (see reference 44 for review). Purified glucocorticoid-receptor complexes bind in vitro with high affinity to specific sites on cloned mouse mammary tumor virus (MTV) DNA (25), whose expression in vivo is glucocorticoid regulated (see reference 29 for review); this is consistent with the view that selective receptor-DNA interactions participate in defining the stringent gene selectivity of hormone responses.The glucocorticoid-receptor complex stimulates the rate of MTV gene transcription in infected cells (31,41,49) by increasing the efficiency of MTV promoter utilization

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“…Our initial experiments were with J2.17, an infected HTC derivative containing a single stably integrated MTV element per cell, which is transcribed only in the presence of dexamethasone (39,53) (Fig. 2c); fragments protected from single-strand-specific -rived by RNA nuclease digestion after hybridization with cellues (see below).…”

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confidence: 99%

Glucocorticoids and chromosomal position modulate murine mammary tumor virus transcription by affecting efficiency of promoter utilization.

Ucker¹,

Firestone²

1983

Mol. Cell. Biol.

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The rate of transcription of murine mammary tumor virus (MTV) sequences in MTV-infected rat hepatoma tissue culture cells is strongly affected by both glucocorticoid hormones and the chromosomal position of provirus integration. We have characterized MTV RNAs produced in J2.17 and M1.54, independent isolates containing, respectively, 1 and 10 proviruses integrated at distinct chromosomal loci. M1.54, but not J2.17, synthesized MTV RNA in the absence of glucocorticoids; the rate of hormone-stimulated viral gene transcription in M1.54 was 50-to 100-fold higher than in J2.17. In each case in which MTV genes were expressed (J2.17 induced, M1.54 basal and induced), the viral RNAs produced were indistinguishable. RNA blotting revealed accumulation of two transcripts, 7.8 and 3.8 kilobases; the latter was likely produced from the former by RNA splicing. Sites used for transcription initiation, polyadenylation, and splicing have been identified from the sizes of end-labeled hybridization probes protected from digestion with mung bean nuclease; the unique initiation and polyadenylation sites were both encoded within the MTV long-terminal-repeat sequence. The efficiencies of splicing and of utilization of the polyadenylation signal did not appear to vary as functions of chromosomal position or hormonal stimulation. Differences in rates of viral gene transcription were reflected in the differential accumulation of the 5'-terminal 136 nucleotides of MTV RNA. Thus, glucocorticoids and chromosomal position appeared to affect solely the efficiency of utilization of the MTV promoter, leaving unchanged the sites of initiation, splicing, and polyadenylation, as well as the efficiencies of the latter two processes.During retrovirus infection, proviral DNA encoding the viral RNA genomes integrates stably in a unique configuration at apparently random sites in the host genome (see reference 51 for review); proviral elements appear to specify at least one transcriptional promoter region which is recognized by host cell machinery. As such, proviral DNAs inserted at distinct chromosomal loci could be used as position-specific probes of cellular transcriptional regulatory mechanisms. in vitro (20,35). The rate of transcription in infected HTC cells is also affected by the chromosomal locus at which the proviral element is integrated (50). This modulatory effect is not a function of the transcriptional activity or hormone responsiveness of the integration region; rather, the chromatin structure of that region appears to specify the structure and the potential for expression of the incoming MTV provirus (16).By what mechanisms do glucocorticoids and chromosomal position exert these effects? In procaryotes, several distinct molecular strategies for regulating transcription have been identified. Thus, one class of regulatory factors directly increases or decreases the efficiency with which RNA polymerase utilizes a given "basal" promoter (37). In other cases, an entirely new "regulated" promoter is activated (8), thereby initiating expressi...

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Integration and transcription of mouse mammary tumor virus DNA in rat hepatoma cells.

Cited by 110 publications

References 27 publications

MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways

MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways

Two classes of mutant mammary tumor virus-infected HTC cell with defects in glucocorticoid-regulated gene expression.

Glucocorticoids and chromosomal position modulate murine mammary tumor virus transcription by affecting efficiency of promoter utilization.

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