scholarly journals Two pathways of p27Kip1degradation are required for murine lymphoma driven by Myc and EBV latent membrane protein 2A

2019 ◽  
Author(s):  
Richard P. Sora ◽  
Masato Ikeda ◽  
Richard Longnecker
Keyword(s):  
Cell Cycle ◽  
Membrane Protein ◽  
Epstein Barr Virus ◽  
Tumor Development ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 2A ◽  
Barr Virus ◽  
Cell Cycle Inhibitor ◽  
Tumor Onset ◽  
Epstein Barr

AbstractEpstein-Barr virus (EBV) latent membrane protein 2A (LMP2A), expressed in EBV latency, contributes to Burkitt Lymphoma (BL) development in a murine model by acting as a constitutively active B cell receptor (BCR) mimic. Mice expressing both LMP2A andMYCtransgenes (LMP2A/λ-MYC) develop tumors significantly faster than mice only expressingMYC(λ-MYC). Previously, we demonstrated the cell cycle inhibitor p27Kip1is present at significantly lower levels in LMP2A/λ-MYCmice due to increased post-translational degradation. P27Kip1degradation can occur in the cytoplasm following phosphorylation on serine 10 (S10), or in the nucleus via the SCFSkp2complex, which depends on Cks1. We previously demonstrated a S10A knock-in of p27Kip1(p27S10A/S10A), which prevented S10 phosphorylation, failed to significantly delay tumor onset in LMP2A/λ-MYCmice. We also previously demonstrated that aCks1knockout partially delayed tumor onset in LMP2A/λ-MYCmice, but onset was still significantly faster than in λ-MYCmice. Here, we have combined both genetic manipulations in what we call p27Supermice. LMP2A/λ-MYC/p27Supermice and λ-MYC/p27Supermice both displayed dramatic delays in tumor onset. Strikingly, tumor development in LMP2A/λ-MYC/p27Supermice was later than in λ-MYCmice and not significantly different from λ-MYC/p27Supermice. The p27Supergenotype also normalized G1-S phase cell cycle progression, spleen size, and splenic architecture in LMP2A/λ-MYCmice. Our results reveal both major pathways of p27Kip1degradation are required for the accelerated BL development driven by LMP2A in our BL model and that blocking both degradation pathways is sufficient to delay Myc-driven tumor development with or without LMP2A.ImportanceBurkitt lymphoma (BL) is a cancer that primarily affects children. The side effects of chemotherapy highlight the need for better BL treatments. Many BL tumors contain Epstein-Barr virus (EBV) and our goal is to determine what makes EBV-positive BL different from EBV-negative BL. This may lead to more specific treatments for both types. All cases of BL require overexpression ofMYC. Mice engineered to express an EBV LMP2A along withMYC(LMP2A/λ-MYCmice) develop tumors much more quickly than mice only expressing MYC (λ-MYCmice). Blocking degradation of the cell cycle inhibitor protein p27Kip1in LMP2A/λ-MYCmice causes tumors to develop later than in λ-MYCmice, showing that p27Kip1degradation may play a larger role in EBV-positive BL than EBV-negative. Furthermore, our studies suggest the cell cycle may be an attractive target as a treatment option for LMP2A positive cancers in humans.

scholarly journals Two Pathways of p27Kip1Degradation Are Required for Murine Lymphoma Driven by Myc and EBV Latent Membrane Protein 2A

mBio ◽  
2019 ◽  
Vol 10 (2) ◽  
Author(s):  
Richard P. Sora ◽  
Masato Ikeda ◽  
Richard Longnecker
Keyword(s):  
Cell Cycle ◽  
Membrane Protein ◽  
Cell Cycle Progression ◽  
Tumor Development ◽  
Cell Receptor ◽  
Latent Membrane Protein ◽  
Phase Cell ◽  
Latent Membrane Protein 2A ◽  
Cell Cycle Inhibitor ◽  
Tumor Onset

ABSTRACTEpstein-Barr virus (EBV) latent membrane protein 2A (LMP2A), expressed in EBV latency, contributes to Burkitt lymphoma (BL) development in a murine model by acting as a constitutively active B cell receptor (BCR) mimic. Mice expressing both LMP2A andMYCtransgenes (LMP2A/λ-MYC) develop tumors significantly faster than mice only expressingMYC(λ-MYC). Previously, we demonstrated the cell cycle inhibitor p27Kip1is present at significantly lower levels in LMP2A/λ-MYCmice due to increased posttranslational degradation. P27Kip1degradation can occur in the cytoplasm following phosphorylation on serine 10 (S10) or in the nucleus via the SCFSkp2complex, which depends on Cks1. We previously demonstrated an S10A knock-in of p27Kip1(p27S10A/S10A) that prevented S10 phosphorylation failed to significantly delay tumor onset in LMP2A/λ-MYCmice. We also previously demonstrated that aCks1knockout partially delayed tumor onset in LMP2A/λ-MYCmice, but onset was still significantly faster than that in λ-MYCmice. Here, we have combined both genetic manipulations in what we call p27Supermice. LMP2A/λ-MYC/p27Supermice and λ-MYC/p27Supermice both displayed dramatic delays in tumor onset. Strikingly, tumor development in LMP2A/λ-MYC/p27Supermice was later than that in λ-MYCmice and not significantly different from that in λ-MYC/p27Supermice. The p27Supergenotype also normalized G1-S-phase cell cycle progression, spleen size, and splenic architecture in LMP2A/λ-MYCmice. Our results reveal both major pathways of p27Kip1degradation are required for the accelerated BL development driven by LMP2A in our BL model and that blocking both degradation pathways is sufficient to delay Myc-driven tumor development with or without LMP2A.IMPORTANCEBL is a cancer that primarily affects children. The side effects of chemotherapy highlight the need for better BL treatments. Many BL tumors contain EBV, and our goal is to determine what makes EBV-positive BL different from EBV-negative BL. This may lead to more specific treatments for both types. All cases of BL require overexpression ofMYC. Mice engineered to express EBV LMP2A along withMYC(LMP2A/λ-MYCmice) develop tumors much more quickly than mice only expressingMYC(λ-MYCmice). Blocking degradation of the cell cycle inhibitor protein p27Kip1in LMP2A/λ-MYCmice causes tumors to develop later than in λ-MYCmice, showing that p27Kip1degradation may play a larger role in EBV-positive BL than EBV-negative BL. Furthermore, our studies suggest the cell cycle is an attractive target as a treatment option for LMP2A-positive cancers in humans.

scholarly journals Epstein-Barr virus in Burkitt’s lymphoma: A role for latent membrane protein 2A

Cell Cycle ◽  
2010 ◽  
Vol 9 (5) ◽  
pp. 901-908 ◽  
Author(s):  
Kathryn T. Bieging ◽  
Michelle Swanson-Mungerson ◽  
Alexandra C. Amick ◽  
Richard Longnecker
Keyword(s):  
Membrane Protein ◽  
Epstein Barr Virus ◽  
Burkitt’S Lymphoma ◽  
Latent Membrane Protein ◽  
Burkitt's Lymphoma ◽  
Latent Membrane Protein 2A ◽  
Barr Virus ◽  
Epstein Barr

scholarly journals Immunohistochemical Detection of the Epstein-Barr Virus–Encoded Latent Membrane Protein 2A in Hodgkin's Disease and Infectious Mononucleosis

Blood ◽  
1997 ◽  
Vol 90 (4) ◽  
pp. 1664-1672 ◽  
Author(s):  
G. Niedobitek ◽  
E. Kremmer ◽  
H. Herbst ◽  
L. Whitehead ◽  
C.W. Dawson ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Protein Expression ◽  
Infectious Mononucleosis ◽  
Epstein Barr Virus ◽  
Hodgkin’S Disease ◽  
Latent Membrane Protein ◽  
Immunohistochemical Detection ◽  
Latent Membrane Protein 2A ◽  
Barr Virus ◽  
Epstein Barr

We describe two new monoclonal antibodies specific for the Epstein-Barr virus (EBV)-encoded latent membrane protein 2A (LMP2A) that are suitable for the immunohistochemical analysis of routinely processed paraffin sections. These antibodies were applied to the immunohistochemical detection of LMP2A in Hodgkin's disease (HD). LMP2A-specific membrane staining was seen in the Hodgkin and Reed-Sternberg (HRS) cells of 22 of 42 (52%) EBV-positive HD cases, but not in 39 EBV-negative HD cases. In lymphoid tissues from patients with acute infectious mononucleosis (IM), interfollicular immunoblasts were shown to express LMP2A. This is the first demonstration of LMP2A protein expression at the single-cell level in EBV-associated lymphoproliferations in vivo. The detection of LMP2A protein expression in HD and IM is of importance in view of the proposed role of this protein for maintaining latent EBV infection and its possible contribution for EBV-associated transformation. Because LMP2A provides target epitopes for EBV-specific cytotoxic T cells, the expression of this protein in HRS cells has implications for the immunotherapeutic approaches to the treatment of HD.

scholarly journals Roles of the ITAM and PY Motifs of Epstein-Barr Virus Latent Membrane Protein 2A in the Inhibition of Epithelial Cell Differentiation and Activation of β-Catenin Signaling

2005 ◽  
Vol 79 (4) ◽  
pp. 2375-2382 ◽  
Author(s):  
Jennifer A. Morrison ◽  
Nancy Raab-Traub
Keyword(s):  
Membrane Protein ◽  
Epstein Barr Virus ◽  
Nuclear Translocation ◽  
Cell Receptor ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 2A ◽  
Barr Virus ◽  
Cellular Processes ◽  
Epstein Barr ◽  
Virus Latent Membrane Protein

ABSTRACT Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A) is important for maintenance of latency in infected B lymphocytes. Through its immunoreceptor tyrosine-based activation motif (ITAM) and PY motifs, LMP2A is able to block B-cell receptor (BCR) signaling, bind BCR-associated kinases, and manipulate the turnover of itself and these kinases via a PY-mediated interaction with the Nedd4 family of ubiquitin ligases. In epithelial cells, LMP2A has been shown to activate the phosphatidylinositol 3′-OH kinase/Akt and β-catenin signaling pathways. In the present study, the biological consequences of LMP2A expression in the normal human foreskin keratinocyte (HFK) cell line were investigated and the importance of the ITAM and PY motifs for LMP2A signaling effects in HFK cells was ascertained. The ITAM was essential for the activation of Akt by LMP2A in HFK cells, while both the ITAM and PY motifs contributed to LMP2A-mediated accumulation and nuclear translocation of the oncoprotein β-catenin. LMP2A inhibited induction of differentiation in an assay conducted with semisolid methylcellulose medium, and the PY motifs were critical for this inhibition. LMP2A is expressed in the EBV-associated epithelial malignancies nasopharyngeal carcinoma and gastric carcinoma, and these data indicate that LMP2A affects cellular processes that likely contribute to carcinogenesis.

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