EBV latent membrane protein 2A orchestrates p27kip1 degradation via Cks1 to accelerate MYC-driven lymphoma in mice

Fish, Kamonwan; Sora, Richard P.; Schaller, Samantha; Longnecker, Richard; Ikeda, Masato

doi:10.1182/blood-2017-07-796821

Cited by 23 publications

(49 citation statements)

References 56 publications

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“…The strongest gene dependency of the TP53wt group was MDM4 (gene score=2.12; Figure 2A, left) that inactivates p53-mediated transcription by blocking of its transactivation domain (Shvarts et al, 1997). Notably, as Epstein-Barr virus (EBV) associated proteins deregulate cell cycle checkpoints and quench the p53 pathway by deubiquitination of the p53 inhibitor MDM2 (Fish et al, 2017;Saha et al, 2009), we confirmed a balanced distribution of EBV infection status among TP53wt and TP53mut BL cell lines (Table S3).…”

Section: P53 Pathway In Blsupporting

confidence: 59%

MDM4 is an essential disease driver targeted by 1q gain in Burkitt lymphoma

Hüllein

Słabicki

Rosołowski³

et al. 2018

Preprint

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Oncogenic MYC activation promotes cellular proliferation in Burkitt lymphoma (BL), but also induces cell cycle arrest and apoptosis mediated by TP53, a tumor suppressor gene that is mutated in 40% of BL cases. To identify therapeutic targets in BL, we investigated molecular dependencies in BL cell lines using RNAi-based, loss-of-function screening. By integrating genotypic and RNAi data, we identified a number of genotype-specific dependencies including the dependence of TCF3/ID3 mutant cell lines on TCF3 and of MYD88 mutant cell lines on TLR signaling. TP53 wild-type (TP53wt) BL were dependent on MDM4, a negative regulator of TP53. In BL cell lines, MDM4 knockdown induced cell cycle arrest and decreased tumor growth in a xenograft model in a p53-dependent manner, while small molecule inhibition of the MDM4-p53 interaction restored p53 activity resulting in cell cycle arrest. Consistent with the pathogenic effect of MDM4 upregulation in BL, we found that TP53wt BL samples were enriched for gain of chromosome 1q which includes the MDM4 locus. 1q gain was also enriched across non-BL cancer cell lines (n=789) without TP53 mutation (23% in TP53wt and 12% in TP53mut, p<0.001). In a set of 216 cell lines representing 19 cancer entities from the Achilles project, MDM4 was the strongest genetic dependency in TP53wt cell lines (p<0.001).Our findings show that in TP53wt BL, MDM4-mediated inhibition of p53 is a mechanism to evade cell cycle arrest. The data highlight the critical role of p53 as a tumor suppressor in BL, and identifies MDM4 as a key functional target of 1q gain in a wide range of cancers, which is therapeutically targetable.

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Section: P53 Pathway In Blsupporting

confidence: 59%

MDM4 is an essential disease driver targeted by 1q gain in Burkitt lymphoma

Hüllein

Słabicki

Rosołowski³

et al. 2018

Preprint

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“…Tumor onset was delayed 315 days in LMP2A/λ- MYC /p27 Super compared to LMP2A/λ- MYC mice. In previous studies, tumor onset was delayed 61.5 days in LMP2A/λ- MYC / Cks1 −/− and not delayed in the LMP2A/λ- MYC /p27 S10A/S10A mice (24, 27). Tumor onset in LMP2A/λ- MYC /p27 Super mice is 172 days later than λ- MYC mice.…”

Section: Resultsmentioning

confidence: 78%

“…Median tumor-free survival time was 378 days in LMP2A/λ- MYC /p27 Super mice compared to 63 in LMP2A/λ- MYC mice, a delay of 315 days. In our previous study, median tumor-free survival in LMP2A/λ- MYC / Cks1 −/− mice was delayed only 61.5 days compared to LMP2A/λ- MYC (27). The S10A knock-in alone was previously shown to have no effect on tumor onset (36 days for both the LMP2A/λ- MYC /p27 S10A/S10A and LMP2A/λ- MYC mice)(24).…”

Section: Resultsmentioning

confidence: 83%

“…Strikingly, tumor onset in the LMP2A/λ- MYC /p27 Super mice was 172 days later than in the λ- MYC mice, and there was no significant difference in tumor onset between the LMP2A/λ- MYC /p27 Super and the λ- MYC /p27 Super mice, which had a median tumor-free survival time of 400 days. In our previous study, tumor onset in LMP2A/λ- MYC / Cks1 −/− mice was 25 days earlier than λ- MYC mice(27). Although the p27 S10A/S10A knock-in by itself was previously shown to have no effect on tumor-free survival(24), our data show that it improved tumor-free survival in the presence of the Cks1 knockout.…”

Section: Resultsmentioning

confidence: 85%

“…Tumor onset in LMP2A/λ- MYC /p27 Super mice is 172 days later than λ- MYC mice. Previously, tumor onset in LMP2A/λ- MYC / Cks1 −/− mice was 25 days earlier than λ- MYC mice(27). Sample size (n) for each genotype is indicated below the curve, as well as p values determined by log-rank (Mantel-Cox) test.…”

Section: Resultsmentioning

confidence: 99%

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Two pathways of p27^Kip1degradation are required for murine lymphoma driven by Myc and EBV latent membrane protein 2A

Longnecker¹,

Ikeda²,

Sora³

2019

Preprint

Self Cite

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27Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A), expressed in EBV 28 latency, contributes to Burkitt Lymphoma (BL) development in a murine model by acting as a 29 constitutively active B cell receptor (BCR) mimic. Mice expressing both LMP2A and MYC 30 transgenes (LMP2A/-MYC) develop tumors significantly faster than mice only expressing MYC 31 (-MYC). Previously, we demonstrated the cell cycle inhibitor p27 Kip1 is present at significantly 32 lower levels in LMP2A/-MYC mice due to increased post-translational degradation. P27 Kip1 33 degradation can occur in the cytoplasm following phosphorylation on serine 10 (S10), or in the 34 nucleus via the SCF Skp2 complex, which depends on Cks1. We previously demonstrated a S10A 35 knock-in of p27 Kip1 (p27 S10A/S10A ), which prevented S10 phosphorylation, failed to significantly 36 delay tumor onset in LMP2A/-MYC mice. We also previously demonstrated that a Cks1 37 knockout partially delayed tumor onset in LMP2A/-MYC mice, but onset was still significantly 38 faster than in -MYC mice. Here, we have combined both genetic manipulations in what we call 39 p27 Super mice. LMP2A/-MYC/p27 Super mice and -MYC/p27 Super mice both displayed dramatic 40 delays in tumor onset. Strikingly, tumor development in LMP2A/-MYC/p27 Super mice was later 41 than in -MYC mice and not significantly different from -MYC/p27 Super mice. The p27 Super 42 genotype also normalized G 1 -S phase cell cycle progression, spleen size, and splenic 43 architecture in LMP2A/-MYC mice. Our results reveal both major pathways of p27 Kip1 44 degradation are required for the accelerated BL development driven by LMP2A in our BL model 45 and that blocking both degradation pathways is sufficient to delay Myc-driven tumor 46 development with or without LMP2A.47 48 Importance 49 Burkitt lymphoma (BL) is a cancer that primarily affects children. The side effects of 50 chemotherapy highlight the need for better BL treatments. Many BL tumors contain Epstein-Barr 51 virus (EBV) and our goal is to determine what makes EBV-positive BL different from EBV-52 negative BL. This may lead to more specific treatments for both types. All cases of BL require 53 overexpression of MYC. Mice engineered to express an EBV LMP2A along with MYC 54 (LMP2A/-MYC mice) develop tumors much more quickly than mice only expressing MYC (-55 MYC mice). Blocking degradation of the cell cycle inhibitor protein p27 Kip1 in LMP2A/-MYC 56 mice causes tumors to develop later than in -MYC mice, showing that p27 Kip1 degradation may 57 play a larger role in EBV-positive BL than EBV-negative. Furthermore, our studies suggest the 58 cell cycle may be an attractive target as a treatment option for LMP2A positive cancers in 59 humans. 60 61 Introduction 62 Epstein-Barr virus (EBV) is a -herpesvirus that establishes latent infection in over 95% 63 of the world's population by adulthood(1). EBV latency occurs primarily in B cells and has been 64 associated with several B cell cancers, including Burkitt Lymphoma (BL)(2). There are thr...

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Biochemical strategies of E3 ubiquitin ligases target viruses in critical diseases

Dubey

Jagtap

Kumar

et al. 2021

J of Cellular Biochemistry

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Viruses are known to cause various diseases in human and also infect other species such as animal plants, fungi, and bacteria. Replication of viruses depends upon their interaction with hosts. Human cells are prone to such unwanted viral infections. Disintegration and reconstitution require host machinery and various macromolecules like DNA, RNA, and proteins are invaded by viral particles. E3 ubiquitin ligases are known for their specific function, that is, recognition of their respective substrates for intracellular degradation. Still, we do not understand how ubiquitin proteasome system-based enzymes E3 ubiquitin ligases do their

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EBV latent membrane protein 2A orchestrates p27kip1 degradation via Cks1 to accelerate MYC-driven lymphoma in mice

Cited by 23 publications

References 56 publications

MDM4 is an essential disease driver targeted by 1q gain in Burkitt lymphoma

MDM4 is an essential disease driver targeted by 1q gain in Burkitt lymphoma

Two pathways of p27^Kip1degradation are required for murine lymphoma driven by Myc and EBV latent membrane protein 2A

Biochemical strategies of E3 ubiquitin ligases target viruses in critical diseases

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EBV latent membrane protein 2A orchestrates p27kip1 degradation via Cks1 to accelerate MYC-driven lymphoma in mice

Cited by 23 publications

References 56 publications

MDM4 is an essential disease driver targeted by 1q gain in Burkitt lymphoma

MDM4 is an essential disease driver targeted by 1q gain in Burkitt lymphoma

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

Biochemical strategies of E3 ubiquitin ligases target viruses in critical diseases

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Two pathways of p27^Kip1degradation are required for murine lymphoma driven by Myc and EBV latent membrane protein 2A