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

Feldman, Daphna; Roniger, Maayan; Bar-Sinai, Allan; Braitbard, Ori; Natan, Carmit; Love, Dona C.; Hanover, John A.; Hochman, Jacob

doi:10.1158/1541-7786.mcr-11-0581

Cited by 25 publications

(43 citation statements)

References 49 publications

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“…demonstrates immune reactivity, including nucleolar localization characteristic of p14 (Figure 2E). Control MCF-7 cells devoid of p14 show no such localization (Figure 2F) (see also Figure 1A insert, and [32]. The correlation observed between the PCR and protein analyses here, is strengthened by our recent findings [8] demonstrating that human salivary glands containing MMTV-env like sequences (using PCR) were also positive for p14 using immunhistochemistry.…”

Section: Resultssupporting

confidence: 76%

“…A similar approach (monoclonal antibody-HIV-Tat conjugate) was employed by us recently to impair the activity of the ABCB1 multi-drug transporter from within drug resistant cells, thus rendering them sensitive to chemotherapy [40]; E) Intracellular introduction of small molecule inhibitors of p14 based on molecular modeling and X-ray crystallography and the role of various mutations along its sequence. For example, based on our recent findings that a point mutation in the CK2 phosphorylation site of p14 results in tumor growth inhibition [32], small molecule inhibitors of CK2 could end up having a similar inhibitory effect in MMTV-associated tumors. By the same token, since a point mutation in the PKC phosphorylation site of p14 enhances tumorigenicity [32], activators of PKC could impair tumor growth.…”

Section: Discussionmentioning

confidence: 99%

“…The epitope recognized by antibody M-66 was mapped (using competition and deletion analyses) to include the region of a functional nuclear localization signal [27]. p14 binds a number of target proteins, among them the nucleolar proteins B23 (Nucleophosmin) and ribosomal protein L5 (RPL5) [32]. The latter, as well as ErbB4, are also transcriptionally regulated by p14 [32].…”

Section: Introductionmentioning

confidence: 99%

“…p14 binds a number of target proteins, among them the nucleolar proteins B23 (Nucleophosmin) and ribosomal protein L5 (RPL5) [32]. The latter, as well as ErbB4, are also transcriptionally regulated by p14 [32]. Subsequent to our initial findings [26] [27], it was demonstrated that this signal peptide plays a key role (analogous to HIV-Rev) as nuclear export factor for intron containing viral transcripts [33] [34], thus defining MMTV as a complex virus.…”

Section: Introductionmentioning

confidence: 99%

“…When mutated in the PKC phosphorylation site, p14 will function as an oncogene, while when mutated in the CK2 site it will function as an anti-oncogene. [32]. …”

Section: Introductionmentioning

confidence: 99%

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A new immunization and treatment strategy for mouse mammary tumor virus (MMTV) associated cancers

et al. 2016

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Mouse Mammary Tumor Virus (MMTV) causes mammary carcinoma or lymphoma in mice. An increasing body of evidence in recent years supports its involvement also in human sporadic breast cancer. It is thus of importance to develop new strategies to impair the development, growth and metastasis of MMTV-associated cancers. The signal peptide of the envelope precursor protein of this virus: MMTV-p14 (p14) is an excellent target for such strategies, due to unique characteristics distinct from its regular endoplasmic reticulum targeting function. These include cell surface expression in: murine cancer cells that harbor the virus, human breast cancer (MCF-7) cells that ectopically express p14, as well as cultured human cells derived from an invasive ductal breast carcinoma positive for MMTV sequences. These findings support its use in signal peptide-based immune targeting. Indeed, priming and boosting mice with p14 elicits a specific anti-signal peptide immune response sufficient for protective vaccination against MMTV-associated tumors. Furthermore, passive immunization using a combination of anti-p14 monoclonal antibodies or the transfer of T-cells from immunized mice (Adoptive Cell Transfer) is also therapeutically effective. With reports demonstrating involvement of MMTV in human breast cancer, we propose the immune-mediated targeting of p14 as a strategy for prevention, treatment and diagnosis of MMTV-associated cancers.

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Section: Resultssupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…When mutated in the PKC phosphorylation site, p14 will function as an oncogene, while when mutated in the CK2 site it will function as an anti-oncogene. [32]. …”

Section: Introductionmentioning

confidence: 99%

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A new immunization and treatment strategy for mouse mammary tumor virus (MMTV) associated cancers

et al. 2016

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The role of BST‐2/Tetherin in host protection and disease manifestation

Mahauad‐Fernandez

Okeoma

2015

Immunity, Inflammation and Disease

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Host cells respond to viral infections by activating immune response genes that are not only involved in inflammation, but may also predispose cells to cancerous transformation. One such gene is BST‐2, a type II transmembrane protein with a unique topology that endows it tethering and signaling potential. Through this ability to tether and signal, BST‐2 regulates host response to viral infection either by inhibiting release of nascent viral particles or in some models inhibiting viral dissemination. However, despite its antiviral functions, BST‐2 is involved in disease manifestation, a function linked to the ability of BST‐2 to promote cell‐to‐cell interaction. Therefore, modulating BST‐2 expression and/or activity has the potential to influence course of disease.

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Revisiting a role for a mammary tumor retrovirus in human breast cancer

Salmons¹,

Günzburg

2013

Intl Journal of Cancer

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There remains great controversy as to whether mouse mammary tumor virus (MMTV), the etiological agent of mammary cancer in mice, or a closely related human retrovirus, plays a role in the development of breast cancer in humans. On one hand, retroviruses such as human T-cell lymphotropic virus and human immunodeficiency virus (HIV) are known causative agents of cancer (in the case of HIV, albeit, indirectly), but attempts to associate other retroviruses with human cancers have been difficult. A recent, high profile, example has been the postulated involvement of another mouse virus, xenotropic murine leukemia virus-related virus, in human prostate cancer, which is now thought to be due to contamination. Here, we review some of the more recent evidence for and against the involvement of MMTV in human breast cancer and suggest future studies that may allow a definitive answer to this conundrum.Mouse mammary tumor virus (MMTV) is the etiological agent of mammary cancer in mice, 1,2 and it has long been postulated that this or a similar, MMTV-related, retrovirus is involved in breast cancer in humans. However, this remains controversial. [3][4][5][6] Indeed, this controversy was one of the reasons for a meeting held in Pisa, Italy organized by Generoso Bevilacqua and his colleagues entitled "viruses and breast cancer" last year. Although retroviruses such as human T-cell lymphotropic virus (HTLV) and human immunodeficiency virus (HIV) are known to be directly or indirectly involved in the causation of cancer, the association of other retroviruses with human cancers has been fraught with difficulties, the most notable and recent of which has been the evidence for xenotropic murine leukemia virus-related virus (XMRV) being associated with prostate cancer, where now the evidence seems to be explainable by the use of contaminated cell's DNA and even contaminated commercially available reagents. 7 The resurgence of interest in a potential role of MMTV in human breast cancer over the last 15 years has been driven by consistent reports that sequences highly homologous to MMTV can be found in up to 40% of human breast cancers, and this data have recently been summarized 8 with some groups even referring to the virus from human tumorderived cells and tissue as HMTV rather than MMTV. Moreover, virus protein expression has been reportedly detected in ten primary cultures of human breast cancer containing MMTV sequences, 9 a putative virus has been isolated and the virus cDNA partially sequenced. 10 MMTV has been shown to be able to infect human cells, 11 where it can randomly integrate its genomic information into the genome of the infected cell, a characteristic step in the retrovirus life cycle, 12 as well as produce infectious progeny capable of spreading. 13 These bona fide integrated proviruses can be detected and isolated from 298 unique integration sites isolated from infected human cells and the integrated proviruses are flanked by a duplicated, five base pair sequence, which is characteristic of MMTV. Moreover, the fla...

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

Cited by 25 publications

References 49 publications

A new immunization and treatment strategy for mouse mammary tumor virus (MMTV) associated cancers

A new immunization and treatment strategy for mouse mammary tumor virus (MMTV) associated cancers

The role of BST‐2/Tetherin in host protection and disease manifestation

Revisiting a role for a mammary tumor retrovirus in human breast cancer

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