Exogenous mouse mammary tumor virus proviral DNA isolated from a kidney adenocarcinoma cell line contains alterations in the U3 region of the long terminal repeat

Wellinger, Raymund J.; Garcia, Madeleine; Vessaz, Annelyse; Diggelmann, Heidi

doi:10.1128/jvi.60.1.1-11.1986

Cited by 48 publications

(27 citation statements)

References 55 publications

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“…In support of this, transcription of acquired MMTV proviruses in EL4 and most lymphomas is not stimulated by the addition of glucocorticoids (9; J. Dudley, unpublished data). MMTV proviruses with deleted LTRs have been described only in T cells and in kidney tumors (9,20,22,27,29,37) and have not been isolated from mammary tumors. Perhaps MMTV transcription is regulated by a different mechanism (factors) in mammary glands and there is no selection for proviruses with deleted LTRs.…”

Section: Discussionmentioning

confidence: 99%

Mouse mammary tumor virus proviruses in T-cell lymphomas lack a negative regulatory element in the long terminal repeat

Hsu

Fabritius

Dudley

1988

J Virol

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The nucleotide sequences of long terminal repeats (LTRs) from several mouse mammary tumor virus (MMTV) proviruses acquired in mouse T-cell lymphomas were determined. All MMTV proviruses cloned from a C57BL/6 lymphoma contained an identical LTR deletion of 491 base pairs (approximately-655 to-165), whereas an MMTV provirus from a BALB/c T-cell lymphoma had a 430-base-pair deletion in the same U3 region. MMTV proviruses with LTR deletions were acquired in these tumors 10 times more frequently than proviruses with intact LTRs. Because the deletions removed a portion of the glucocorticoid response element or "regulated" enhancer, the transcriptional activity of the deleted MMTV LTRs was assessed in both transient expression and stable transfection experiments. Plasmids were constructed in which the deleted or full-length MMTV LTRs were placed upstream of the chloramphenicol acetyltransferase gene. Results from transfection experiments with these constructs showed that the basal expression of the deleted MMTV LTR in the absence of glucocorticoids was higher than that of the full-length Mtv-17 or C3H MMTV LTRs under the same conditions. Moreover, the C3H LTR with a similar deletion (-637 to-255) also promoted high basal

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Section: Discussionmentioning

confidence: 99%

Mouse mammary tumor virus proviruses in T-cell lymphomas lack a negative regulatory element in the long terminal repeat

Hsu

Fabritius

Dudley

1988

J Virol

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“…In general, MMTVinfected B cells and dendritic cells do not undergo malignant transformation (7,10). Instead, B cells generate virus particles that, upon transfer to mammary epithelial cells, result in the transformation of these secondary targets (11). In the absence of B cells, the mammary epithelial cells of mice exposed to MMTV are not infected and do not form tumors (12).…”

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confidence: 99%

MMTV Env encodes an ITAM responsible for transformation of mammary epithelial cells in three-dimensional culture

Katz

Lareef

Rassa

et al. 2005

The Journal of Experimental Medicine

105

123

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Expression of immunoreceptor tyrosine-based activation motif (ITAM)-containing signaling proteins is normally restricted to hematopoietic tissues. The basal activity of ITAM-containing proteins is mediated through negative regulation by coreceptors restricted to hematopoietic tissues. We have identified an ITAM signaling domain encoded within the env gene of murine mammary tumor virus (MMTV). Three-dimensional structures derived in vitro from murine cells stably transfected with MMTV env display a depolarized morphology in comparison with control mammary epithelial cells. This effect is abolished by Y>F substitution within the Env ITAM, as well as inhibitors of Syk and Src protein tyrosine kinases. Env-expressing cells bear hallmarks of cell transformation such as sensitivity to apoptosis induced by tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) or TNFα, as well as down-regulation of E-cadherin and Keratin-18. Human normal mammary epithelial cells expressing MMTV Env also develop transformed phenotype, as typified by growth in soft agar and Matrigel invasion. These disruptions are abrogated by Y>F substitutions. We conclude that ITAM-dependent signals are generated through MMTV Env and trigger early hallmarks of transformation of mouse and human mammary epithelial cells. Therefore, these data suggest a heretofore unappreciated potential mechanism for the initiation of breast cancer and identify MMTV Env and ITAM-containing proteins in human breast tumors as probable oncoproteins.

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“…The presence of additional regulatory elements for MMTV transcription first was suggested by the isolation of MMTV LTR variants from T-cell tumors (1,16,21,24,29,30) as well as kidney, testicular, and pituitary tumors of mice (44,56). In each case, the acquired MMTV proviruses in these tumors had sustained large (approximately 350-to 500-bp) deletions within the LTR (1,16,21,24,29).…”

mentioning

confidence: 99%

A redundant nuclear protein binding site contributes to negative regulation of the mouse mammary tumor virus long terminal repeat

Bramblett

Hsu

Lozano

et al. 1995

J Virol

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The tissue specificity of mouse mammary tumor virus (MMTV) expression is controlled by regulatory elements in the MMTV long terminal repeat (LTR). These regulatory elements include the hormone response element, located approximately between ؊200 and ؊75, as well as binding sites for NF-1, Oct-1 (OTF-1), and mammary gland enhancer factors. Naturally occurring MMTV deletion variants isolated from T-cell and kidney tumors, transgenic-mouse experiments with MMTV LTR deletions, and transient transfection assays with LTR constructs indicate that there are additional transcription regulatory elements, including a negative regulatory element (NRE), located upstream of the hormone response element. To further define this regulatory region, we have constructed a series of BAL 31 deletion mutants in the MMTV LTR for use in transient transfection assays. These assays indicated that deletion of two regions (referred to as promoter-distal and -proximal NREs) between ؊637 and ؊201 elevated basal MMTV promoter activity in the absence of glucocorticoids. The region between ؊637 and ؊264 was surveyed for the presence of nuclear protein binding sites by gel retardation assays. Only one type of protein complex (referred to as NRE-binding protein or NBP) bound exclusively to sites that mapped to the promoter-distal and -proximal NREs identified by BAL 31 mutations. The promoter-proximal binding site was mapped further by linker substitution mutations and transfection assays. Mutations that mapped to a region containing an inverted repeat beginning at ؊287 relative to the start of transcription elevated basal expression of a reporter gene driven by the MMTV LTR. A 59-bp DNA fragment from the distal NRE also bound the NBP complex. Gel retardation assays showed that mutations within both inverted repeats of the proximal NRE eliminated NBP binding and mutations within single repeats altered NBP binding. Intriguingly, the NBP complex was detected in extracts from T cells and lung cells but was absent from mammary gland cells. These results suggest that a factor contributing to high-level expression of MMTV in the mammary gland is the lack of negative regulation by NBP.

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Exogenous mouse mammary tumor virus proviral DNA isolated from a kidney adenocarcinoma cell line contains alterations in the U3 region of the long terminal repeat

Cited by 48 publications

References 55 publications

Mouse mammary tumor virus proviruses in T-cell lymphomas lack a negative regulatory element in the long terminal repeat

Mouse mammary tumor virus proviruses in T-cell lymphomas lack a negative regulatory element in the long terminal repeat

MMTV Env encodes an ITAM responsible for transformation of mammary epithelial cells in three-dimensional culture

A redundant nuclear protein binding site contributes to negative regulation of the mouse mammary tumor virus long terminal repeat

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