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

Blood
Kamonwan FishMasato Ikeda

Abstract

Epstein-Barr virus (EBV) establishes lifelong infection in B lymphocytes of most human hosts and is associated with several B lymphomas. During latent infection, EBV encodes latent membrane protein 2A (LMP2A) to promote the survival of B cells by mimicking host B-cell receptor signaling. By studying the roles of LMP2A during lymphoma development in vivo, we found that LMP2A mediates rapid MYC-driven lymphoma onset by allowing B cells to bypass MYC-induced apoptosis mediated by the p53 pathway in our transgenic mouse model. However, the mechanisms used by LMP2A to facilitate transformation remain elusive. In this study, we demonstrate a key role of LMP2A in promoting hyperproliferation of B cells by enhancing MYC expression and MYC-dependent degradation of the p27kip1 tumor suppressor. Loss of the adaptor protein cyclin-dependent kinase regulatory subunit 1 (Cks1), a cofactor of the SCFSkp2 ubiquitin ligase complex and a downstream target of MYC, increases p27kip1 expression during a premalignant stage. In mice that express LMP2A, Cks1 deficiency reduces spleen weights, restores B-cell follicle formation, impedes cell cycle progression of pretumor B cells, and eventually prolongs MYC-driven tumor onset. This study demonstrates t...Continue Reading

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Citations

Nov 6, 2018·Medical Microbiology and Immunology·Huali YinRunliang Gan
May 10, 2019·Expert Opinion on Therapeutic Patents·Xiao-Na WangTian-Miao Ou
Mar 16, 2019·Frontiers in Oncology·Kwai Fung HuiAlan Kwok Shing Chiang
Mar 18, 2020·Frontiers in Cell and Developmental Biology·Tiziana VescovoManuela Antonioli
Oct 7, 2020·Proceedings of the National Academy of Sciences of the United States of America·Kamonwan FishThomas Oellerich
Mar 26, 2021·Frontiers in Oncology·Alejandra SuaresOmar Coso
Jun 3, 2021·Pathogens·Martin A Prusinkiewicz, Joe S Mymryk
Sep 15, 2021·Journal of Cellular Biochemistry·Ankur R DubeyAmit Mishra
Feb 3, 2022·PLoS Pathogens·Eric M Burton, Benjamin E Gewurz

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