Regulation of Wee1 by PRMT5 in Brain Tumors

Abstract

The eukaryotic cell cycle is characterized by a series of tightly orchestrated events during which cellular components are replicated and subsequently divided. In mammalian cells, the precise spatiotemporal control of cell cycle progression is achieved through multiple cyclin-dependent-kinases (Cdks), which are pivotal for both the proper timing of the cell cycle and the maintenance of genomic integrity. The cell progresses through a series of different phases before division, including the pre-mitotic G2 phase and the mitotic M phase. As the interval between DNA replication and mitosis, G2 phase is the stage where protein synthesis occurs in preparation for mitosis. On the other hand, mitosis is characterized by the most dramatic events of the cell cycle, featuring chromosome condensation and segregation into two daughter cells. Transition from G2 to M phase is driven by the activation of Cdk1, which forms a heterodimer with its obligate allosteric activator Cyclin B1. This heterodimer phosphorylates downstream effectors, thereby inducing entry into mitosis. Entry into mitosis is halted by activation of the G2/M cell cycle checkpoint, which stimulates the Myt1 and Wee1 kinases; these activated kinases phosphorylate Cdk1 at Thr14 and Tyr15, resulting in Cdk1 inactivation. Failure of G2/M cell cycle arrest leads to premature mitosis and triggers a form of cell death marked by multiple micronuclei and decondensed chromatin known as "mitotic catastrophe". Mitotic catastrophe can be stimulated by the presence of incompletely replicated DNA or DNA damage, which leads to the unscheduled activation of the Cdk1/CyclinB complex.Recent studies in the brain tumor glioblastoma (GBM) have suggested that abrogation of the G2/M checkpoint with a Wee1 inhibitor enhances the efficacy of chemotherapy and ionizing radiation[1]. Interestingly, I have found that Wee1 protein levels vary dramatically between different types of brain tumors including glioblastoma and medulloblastoma. Also, Wee1 protein abundance determines tumor sensitivity to DNA-damaging chemotherapies. Furthermore, similar to findings in the Xenopus egg extract, in a mammalian cell culture system I have found that Wee1 protein abundance is subject to regulation by the arginine methyltransferase PRMT5. Taken together, these findings suggest that Wee1 or PRMT5 may be used as effective targets for therapy in a subset of glioblastoma and medulloblastoma patients. 1. Mir, S.E., et al., In Silico Analysis of Kinase Expression Identifies WEE1 as a Gatekeeper against Mitotic Catastrophe in Glioblastoma. Cancer Cell, 2010. 18(3): p. 244-257.