| First Author | Sora RP | Year | 2019 |
| Journal | mBio | Volume | 10 |
| Issue | 2 | PubMed ID | 30992353 |
| Mgi Jnum | J:291663 | Mgi Id | MGI:6443098 |
| Doi | 10.1128/mBio.00548-19 | Citation | Sora RP, et al. (2019) Two Pathways of p27(Kip1) Degradation Are Required for Murine Lymphoma Driven by Myc and EBV Latent Membrane Protein 2A. mBio 10(2) |
| abstractText | 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/lambda-MYC) develop tumors significantly faster than mice only expressing MYC (lambda-MYC). Previously, we demonstrated the cell cycle inhibitor p27(Kip1) is present at significantly lower levels in LMP2A/lambda-MYC mice due to increased posttranslational degradation. P27(Kip1) degradation can occur in the cytoplasm following phosphorylation on serine 10 (S10) or in the nucleus via the SCF(Skp2) complex, which depends on Cks1. We previously demonstrated an S10A knock-in of p27(Kip1) (p27(S10A/S10A)) that prevented S10 phosphorylation failed to significantly delay tumor onset in LMP2A/lambda-MYC mice. We also previously demonstrated that a Cks1 knockout partially delayed tumor onset in LMP2A/lambda-MYC mice, but onset was still significantly faster than that in lambda-MYC mice. Here, we have combined both genetic manipulations in what we call p27(Super) mice. LMP2A/lambda-MYC/p27(Super) mice and lambda-MYC/p27(Super) mice both displayed dramatic delays in tumor onset. Strikingly, tumor development in LMP2A/lambda-MYC/p27(Super) mice was later than that in lambda-MYC mice and not significantly different from that in lambda-MYC/p27(Super) mice. The p27(Super) genotype also normalized G1-S-phase cell cycle progression, spleen size, and splenic architecture in LMP2A/lambda-MYC mice. Our results reveal both major pathways of p27(Kip1) 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/lambda-MYC mice) develop tumors much more quickly than mice only expressing MYC (lambda-MYC mice). Blocking degradation of the cell cycle inhibitor protein p27(Kip1) in LMP2A/lambda-MYC mice causes tumors to develop later than in lambda-MYC mice, showing that p27(Kip1) 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. |
