Mouse Mammary Tumor Virus Suppresses Apoptosis of Mammary Epithelial Cells through ITAM-Mediated Signaling

Kim, Hyoung H.; Grande, Shannon; Monroe, John G.; Ross, Susan R.

doi:10.1128/jvi.02029-12

Cited by 13 publications

(8 citation statements)

References 53 publications

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“…Although the results reported here demonstrate that the 2 ITAM stimulates Syk activation of NF- B, 2-stimulated Syk also may activate other transcription factors. Although viral ITAMs are most often associated with oncogenesis (11,52,53,(60)(61)(62), reovirus is not oncogenic. There are two nononcogenic viruses known to encode ITAM-containing proteins: hantavirus and SIV.…”

Section: Discussionmentioning

confidence: 99%

An ITAM in a Nonenveloped Virus Regulates Activation of NF-κB, Induction of Beta Interferon, and Viral Spread

Stebbing

Irvin

Rivera-Serrano

et al. 2014

J Virol

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Immunoreceptor tyrosine-based activation motifs (ITAMs) are signaling domains located within the cytoplasmic tails of many transmembrane receptors and associated adaptor proteins that mediate immune cell activation. ITAMs also have been identified in the cytoplasmic tails of some enveloped virus glycoproteins. Here, we identified ITAM sequences in three mammalian reovirus proteins: 2, 2, and 2. We demonstrate for the first time that 2 is phosphorylated, contains a functional ITAM, and activates NF-B. Specifically, 2 and NS recruit the ITAM-signaling intermediate Syk to cytoplasmic viral factories and this recruitment requires the 2 ITAM. Moreover, both the 2 ITAM and Syk are required for maximal 2 activation of NF-B. A mutant virus lacking the 2 ITAM activates NF-B less efficiently and induces lower levels of the downstream antiviral cytokine beta interferon (IFN-␤) than does wild-type virus despite similar replication. Notably, the consequences of these 2 ITAM effects are cell type specific. In fibroblasts where NF-B is required for reovirus-induced apoptosis, the 2 ITAM is advantageous for viral spread and enhances viral fitness. Conversely, in cardiac myocytes where the IFN response is critical for antiviral protection and NF-B is not required for apoptosis, the 2 ITAM stimulates cellular defense mechanisms and diminishes viral fitness. Together, these results suggest that the cell type-specific effect of the 2 ITAM on viral spread reflects the cell type-specific effects of NF-B and IFN-␤. This first demonstration of a functional ITAM in a nonenveloped virus presents a new mechanism for viral ITAM-mediated signaling with likely organ-specific consequences in the host.

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Section: Discussionmentioning

confidence: 99%

An ITAM in a Nonenveloped Virus Regulates Activation of NF-κB, Induction of Beta Interferon, and Viral Spread

Stebbing

Irvin

Rivera-Serrano

et al. 2014

J Virol

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“…Studies from the Ross Lab have been instrumental in deciphering the roles of restriction factors and other host proteins in Mouse mammary tumor virus (MMTV)‐induced mammary oncogenesis 176, 177, 178, 179, 180. Sequences similar to MMTV are present in human breast tumors 181, 182, 183 and cultures of human breast cancer cells produce human mammary tumor virus (HMTV) with morphologic and molecular characteristics of MMTV and with 95% homology with MMTV 184.…”

Section: Regulation Of Bst‐2 By Oncogenic Virusesmentioning

confidence: 99%

“…In cancer, BST-2 expression is epigenetically regulated by hypomethylation of specific CpGs, by TGF-b signaling, and by yet to identified mechanisms during viral carcinogenesis (unknown). mammary oncogenesis [176][177][178][179][180]. Sequences similar to MMTV are present in human breast tumors [181][182][183] and cultures of human breast cancer cells produce human mammary tumor virus (HMTV) with morphologic and molecular characteristics of MMTV and with 95% homology with MMTV [184].…”

Section: Regulation Of Bst-2 By Oncogenic Virusesmentioning

confidence: 99%

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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“…MMTV expressing cells escape apoptosis by activation of immune receptor tyrosine kinase-based activation motif-mediated Src tyrosine kinase signalling pathways [67]. EBV (68%), HPV (50%) and MMTV (78%) gene sequences are present and co-exist in many human breast cancers.…”

Section: Introductionmentioning

confidence: 99%

Role of viruses in the development of breast cancer

Alibek

Kakpenova

Mussabekova

et al. 2013

Infect Agents Cancer

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The most common cancer worldwide among women is breast cancer. The initiation, promotion, and progression of this cancer result from both internal and external factors. The International Agency for Research on Cancer stated that 18-20% of cancers are linked to infection, and the list of definite, probable, and possible carcinogenic agents is growing each year. Among them, biological carcinogens play a significant role. In this review, data covering infection-associated breast and lung cancers are discussed and presented as possible involvements as pathogens in cancer. Because carcinogenesis is a multistep process with several contributing factors, we evaluated to what extent infection is significant, and concluded that members of the herpesvirus, polyomavirus, papillomavirus, and retrovirus families definitely associate with breast cancer. Detailed studies of viral mechanisms support this conclusion, but have presented problems with experimental settings. It is apparent that more effort needs to be devoted to assessing the role of these viruses in carcinogenesis, by characterizing additional confounding and synergistic effects of carcinogenic factors. We propose that preventing and treating infections may possibly stop or even eliminate certain types of cancers.

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Mouse Mammary Tumor Virus Suppresses Apoptosis of Mammary Epithelial Cells through ITAM-Mediated Signaling

Cited by 13 publications

References 53 publications

An ITAM in a Nonenveloped Virus Regulates Activation of NF-κB, Induction of Beta Interferon, and Viral Spread

An ITAM in a Nonenveloped Virus Regulates Activation of NF-κB, Induction of Beta Interferon, and Viral Spread

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

Role of viruses in the development of breast cancer

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