MMTV Infectious Cycle and the Contribution of Virus-encoded Proteins to Transformation of Mammary Tissue

Ross, Susan R.

doi:10.1007/s10911-008-9090-8

Cited by 34 publications

(30 citation statements)

References 79 publications

(85 reference statements)

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“…They showed that ectopic expression of MMTV Env in normal mammary epithelial cells resulted in phenotypic transformation, and an activation motif in this protein (the Immunoreceptor Tyrosine-based Activation Motif -ITAM) was critical to that activity. Although subsequent studies (using Env expression in transgenic mice) indicated that ITAM is not sufficient for cellular transformation, Env signaling, nevertheless, takes part in MMTVmediated transformation, as mutation of the ITAM reduces virus-induced mammary tumorigenesis (48,49). Taken together, our findings and those of Ross's group are consistent with a role for the Env protein and its signal peptide in regulating the tumorigenic potential of MMTV-infected cells.…”

Section: Discussionsupporting

confidence: 83%

The Signal Peptide of Mouse Mammary Tumor Virus-Env: A Phosphoprotein Tumor Modulator

Feldman

Roniger

Bar-Sinai

et al. 2012

Molecular Cancer Research

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Mouse mammary tumor virus (MMTV) is associated primarily with mammary carcinomas and lymphomas. The signal peptide of the MMTV envelope precursor is uniquely targeted to nucleoli of cells that harbor the virus, where it can function as a nuclear export factor for intron-containing transcripts. Antibodies to this signal peptide, which we refer to as p14, were previously shown to label nucleoli in a subset of human breast cancers. To look for additional cellular functions of p14, different mutants were ectopically expressed in the MCF-7 human breast cancer cell line. This approach identified motifs responsible for its nucleolar targeting, nucleocytoplasmic shuttling, target protein (B23, nucleophosmin) binding, and phosphorylation at serine 18 and 65 both in situ and in vitro. To test the role of these phosphorylation sites, we carried out in vivo tumorigenesis studies in severe combined immunodeficient mice. The findings show that the p14-Ser65Ala mutation is associated with impaired tumorigenicity, whereas the p14-Ser18Ala mutation is associated with enhanced tumorigenicity. Microarray analysis suggests that phosphorylation at serine 18 or at serine 65 is associated with transcriptional regulation of the L5 nucleolar ribosomal protein (a p14 target) and the Erb-B signal transduction pathway. Taken together, these results show that the phosphorylation status of p14 determines whether it functions as a pro-oncogenic or antioncogenic modulator.

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Section: Discussionsupporting

confidence: 83%

The Signal Peptide of Mouse Mammary Tumor Virus-Env: A Phosphoprotein Tumor Modulator

Feldman

Roniger

Bar-Sinai

et al. 2012

Molecular Cancer Research

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“…Resistance is due in most cases to lack of infection or virus spread within the lymphoid compartment. The MMTV genome encodes a superantigen (Sag) protein which is presented by major histocompatibility complex (MHC) class II molecules on antigenpresenting cells, such as DCs, to T cells, thereby inducing their activation (34). Activated T cells in turn activate bystander antigen-presenting cells, ultimately resulting in virus amplification in the lymphoid compartment.…”

Section: Discussionmentioning

confidence: 99%

Expression of Murine APOBEC3 Alleles in Different Mouse Strains and Their Effect on Mouse Mammary Tumor Virus Infection

Okeoma

Petersen

Ross

2009

J Virol

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Recent work has shown that mouse APOBEC3 restricts infection by mouse mammary tumor virus (MMTV) and murine leukemia virus (MLV) and that there are polymorphic APOBEC3 alleles found in different inbred mouse strains. For example, C57BL/6 mice, which are resistant to Friend MLV (F-MLV), encode a APOBEC3 gene different from that encoded by F-MLV-susceptible BALB/c mice; the predominant RNA produced in C57BL/6 mice lacks exon 5 (mA3 ؊5 ) and encodes a protein with 15 polymorphic amino acids. It has also been reported that BALB/c mice produce only a variant RNA that lacks exon 2 (mA3 ؊2 ). In this study, we examined the effect of these polymorphic APOBEC3 proteins on MMTV infection. We found that the major RNA made in C57BL/6 and B10.BR mice lacks exon 5 but that BALB/c and C3H/HeN mice predominantly express an RNA that contains all nine exons. In addition to producing the splice variant, C57BL/6 and B10.BR cells and tissues had levels of mA3 RNA fivefold higher than those from BALB/c and C3H/HeN mice. A cloned C57BL/6-derived mA3 protein lacking exon 5 inhibited MMTV infection better than a cloned full-length protein derived from 129/Ola RNA when packaged into MMTV virions. We also tested dendritic cells derived from different inbred mouse strains for their abilities to be infected by MMTV and showed that susceptibility to infection correlated with the presence of the exon 5-encoding allele. In vivo susceptibility to infection cosegregated with the inherited mA3 allele in a C57BL/6 ؋ BALB/c backcross analysis. Moreover, virus produced in vivo in the mammary tissue of mA3 knockout and BALB/c mice was more infectious than that produced in the tissue of C57BL/6 mice. These data indicate that mA3 plays a role in the genetics of susceptibility and resistance to MMTV infection.

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“…The HERV-K (HML-2) proviruses (4-9), so-named for their use of a Lys tRNA primer and similarity to the mouse mammary tumor virus (human MMTV like) (10), represent an exception to the antiquity of most HERVs. HML-2 has contributed to at least 120 human-specific insertions, and population-based surveys indicate as many as 15 unfixed sites, including 11 loci with more or less full-length proviruses (5,6,8,9).…”

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confidence: 99%

Discovery of unfixed endogenous retrovirus insertions in diverse human populations

Wildschutte

Williams

Montesion

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

240

304

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Endogenous retroviruses (ERVs) have contributed to more than 8% of the human genome. The majority of these elements lack function due to accumulated mutations or internal recombination resulting in a solitary (solo) LTR, although members of one group of human ERVs (HERVs), HERV-K, were recently active with members that remain nearly intact, a subset of which is present as insertionally polymorphic loci that include approximately full-length (2-LTR) and solo-LTR alleles in addition to the unoccupied site. Several 2-LTR insertions have intact reading frames in some or all genes that are expressed as functional proteins. These properties reflect the activity of HERV-K and suggest the existence of additional unique loci within humans. We sought to determine the extent to which other polymorphic insertions are present in humans, using sequenced genomes from the 1000 Genomes Project and a subset of the Human Genome Diversity Project panel. We report analysis of a total of 36 nonreference polymorphic HERV-K proviruses, including 19 newly reported loci, with insertion frequencies ranging from <0.0005 to >0.75 that varied by population. Targeted screening of individual loci identified three new unfixed 2-LTR proviruses within our set, including an intact provirus present at Xq21.33 in some individuals, with the potential for retained infectivity.

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MMTV Infectious Cycle and the Contribution of Virus-encoded Proteins to Transformation of Mammary Tissue

Cited by 34 publications

References 79 publications

The Signal Peptide of Mouse Mammary Tumor Virus-Env: A Phosphoprotein Tumor Modulator

The Signal Peptide of Mouse Mammary Tumor Virus-Env: A Phosphoprotein Tumor Modulator

Expression of Murine APOBEC3 Alleles in Different Mouse Strains and Their Effect on Mouse Mammary Tumor Virus Infection

Discovery of unfixed endogenous retrovirus insertions in diverse human populations

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