Two Pathways of p27<sup>Kip1</sup> Degradation Are Required for Murine Lymphoma Driven by Myc and EBV Latent Membrane Protein 2A

ABSTRACT Epstein-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 and MYC transgenes (LMP2A/λ-MYC) develop tum...

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Autores principales:	Richard P. Sora, Masato Ikeda, Richard Longnecker
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Burkitt lymphoma Epstein-Barr virus LMP2A Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/efb903ff4448408aa638abfe735e43b4
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spelling	oai:doaj.org-article:efb903ff4448408aa638abfe735e43b42021-11-15T15:55:24ZTwo Pathways of p27<sup>Kip1</sup> Degradation Are Required for Murine Lymphoma Driven by Myc and EBV Latent Membrane Protein 2A10.1128/mBio.00548-192150-7511https://doaj.org/article/efb903ff4448408aa638abfe735e43b42019-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00548-19https://doaj.org/toc/2150-7511ABSTRACT Epstein-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 and MYC transgenes (LMP2A/λ-MYC) develop tumors significantly faster than mice only expressing MYC (λ-MYC). Previously, we demonstrated the cell cycle inhibitor p27Kip1 is present at significantly lower levels in LMP2A/λ-MYC mice due to increased posttranslational degradation. P27Kip1 degradation can occur in the cytoplasm following phosphorylation on serine 10 (S10) or in the nucleus via the SCFSkp2 complex, 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-MYC mice. We also previously demonstrated that a Cks1 knockout partially delayed tumor onset in LMP2A/λ-MYC mice, but onset was still significantly faster than that in λ-MYC mice. Here, we have combined both genetic manipulations in what we call p27Super mice. LMP2A/λ-MYC/p27Super mice and λ-MYC/p27Super mice both displayed dramatic delays in tumor onset. Strikingly, tumor development in LMP2A/λ-MYC/p27Super mice was later than that in λ-MYC mice and not significantly different from that in λ-MYC/p27Super mice. The p27Super genotype also normalized G1-S-phase cell cycle progression, spleen size, and splenic architecture in LMP2A/λ-MYC mice. Our results reveal both major pathways of p27Kip1 degradation 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. IMPORTANCE BL 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 of MYC. Mice engineered to express EBV LMP2A along with MYC (LMP2A/λ-MYC mice) develop tumors much more quickly than mice only expressing MYC (λ-MYC mice). Blocking degradation of the cell cycle inhibitor protein p27Kip1 in LMP2A/λ-MYC mice causes tumors to develop later than in λ-MYC mice, showing that p27Kip1 degradation 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.Richard P. SoraMasato IkedaRichard LongneckerAmerican Society for MicrobiologyarticleBurkitt lymphomaEpstein-Barr virusLMP2AMicrobiologyQR1-502ENmBio, Vol 10, Iss 2 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Burkitt lymphoma Epstein-Barr virus LMP2A Microbiology QR1-502
spellingShingle	Burkitt lymphoma Epstein-Barr virus LMP2A Microbiology QR1-502 Richard P. Sora Masato Ikeda Richard Longnecker Two Pathways of p27<sup>Kip1</sup> Degradation Are Required for Murine Lymphoma Driven by Myc and EBV Latent Membrane Protein 2A
description	ABSTRACT Epstein-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 and MYC transgenes (LMP2A/λ-MYC) develop tumors significantly faster than mice only expressing MYC (λ-MYC). Previously, we demonstrated the cell cycle inhibitor p27Kip1 is present at significantly lower levels in LMP2A/λ-MYC mice due to increased posttranslational degradation. P27Kip1 degradation can occur in the cytoplasm following phosphorylation on serine 10 (S10) or in the nucleus via the SCFSkp2 complex, 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-MYC mice. We also previously demonstrated that a Cks1 knockout partially delayed tumor onset in LMP2A/λ-MYC mice, but onset was still significantly faster than that in λ-MYC mice. Here, we have combined both genetic manipulations in what we call p27Super mice. LMP2A/λ-MYC/p27Super mice and λ-MYC/p27Super mice both displayed dramatic delays in tumor onset. Strikingly, tumor development in LMP2A/λ-MYC/p27Super mice was later than that in λ-MYC mice and not significantly different from that in λ-MYC/p27Super mice. The p27Super genotype also normalized G1-S-phase cell cycle progression, spleen size, and splenic architecture in LMP2A/λ-MYC mice. Our results reveal both major pathways of p27Kip1 degradation 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. IMPORTANCE BL 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 of MYC. Mice engineered to express EBV LMP2A along with MYC (LMP2A/λ-MYC mice) develop tumors much more quickly than mice only expressing MYC (λ-MYC mice). Blocking degradation of the cell cycle inhibitor protein p27Kip1 in LMP2A/λ-MYC mice causes tumors to develop later than in λ-MYC mice, showing that p27Kip1 degradation 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.
format	article
author	Richard P. Sora Masato Ikeda Richard Longnecker
author_facet	Richard P. Sora Masato Ikeda Richard Longnecker
author_sort	Richard P. Sora
title	Two Pathways of p27<sup>Kip1</sup> Degradation Are Required for Murine Lymphoma Driven by Myc and EBV Latent Membrane Protein 2A
title_short	Two Pathways of p27<sup>Kip1</sup> Degradation Are Required for Murine Lymphoma Driven by Myc and EBV Latent Membrane Protein 2A
title_full	Two Pathways of p27<sup>Kip1</sup> Degradation Are Required for Murine Lymphoma Driven by Myc and EBV Latent Membrane Protein 2A
title_fullStr	Two Pathways of p27<sup>Kip1</sup> Degradation Are Required for Murine Lymphoma Driven by Myc and EBV Latent Membrane Protein 2A
title_full_unstemmed	Two Pathways of p27<sup>Kip1</sup> Degradation Are Required for Murine Lymphoma Driven by Myc and EBV Latent Membrane Protein 2A
title_sort	two pathways of p27<sup>kip1</sup> degradation are required for murine lymphoma driven by myc and ebv latent membrane protein 2a
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/efb903ff4448408aa638abfe735e43b4
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Two Pathways of p27<sup>Kip1</sup> Degradation Are Required for Murine Lymphoma Driven by Myc and EBV Latent Membrane Protein 2A

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