Medulloblastoma (MB) is the most common pediatric central-nervous-system malignancy. In a new study, Huang et al. identified by microarray analysis the EAG2 voltage-gated potassium channel as being highly overexpressed in tumor cells derived from MB mouse models. Molecular and electrophysiological analyses verified the abundance of EAG2 protein and potassium channel activity in mouse MB cells. EAG2 overexpression was also found to be a hallmark of a significant subset of human MBs across three of four MB molecular subgroups. RNAi-mediated knockdown of EAG2 resulted in impaired MB cell growth in vitro, and it reduced MB cell tumorigenicity and improved survival in tumor-bearing mice. To understand the mechanism underlying the role of EAG2 in cell growth, Huang et al. investigated the subcellular localization of EAG2, which was found to relocate to the plasma membrane during mitosis. This shift in EAG2's membrane localization was accompanied by a higher outward potassium-current density. EAG2 knockdown also resulted in MB cell-cycle arrest in late G2 phase, and cells showed aberrant premitotic cytoplasmic condensation, mitotic catastrophe and reduced cyclin B1 expression. The authors hypothesized that EAG2 may function to regulate cell volume during cell-cycle progression, which was indeed the case, as EAG2 knockdown resulted in a striking increase in cell volume in late G2 phase. So how does the increased cell volume in EAG2-depleted cells cause cell-cycle arrest? The increased cell volume of EAG2 knockdown cells triggered p38 MAPK activation, which responds to stress stimuli such as hypotonic stress and is known to induce G2-M cell cycle arrest. In contrast, inhibition of the p38 MAPK pathway significantly rescued the growth defect and G2 arrest. Altogether, these findings identify EAG2 as a promising new therapeutic target in human MB. (Genes Dev. doi:10.1101/gad.193789.112, published online 1 Aug 2012)