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KV10.1 is a voltage-gated potassium channel expressed selectively in the mammalian brain but also aberrantly in cancer cells. In this study we identified short splice variants of KV10.1 resulting from exon-skipping events (E65 and E70) in human brain and cancer cell lines. The presence of the variants was confirmed by Northern blot and RNase protection assays. Both variants completely lacked the transmembrane domains of the channel and produced cytoplasmic proteins without channel function. In a reconstituted system, both variants co-precipitated with the full-length channel and induced a robust down-regulation of KV10.1 current when co-expressed with the full-length form, but their effect was mechanistically different. E65 required a tetramerization domain and induced a reduction in the overall expression of full-length KV10.1, whereas E70 mainly affected its glycosylation pattern. E65 triggered the activation of cyclin-dependent kinases in Xenopus laevis oocytes, suggesting a role in cell cycle control. Our observations highlight the relevance of noncanonical functions for the oncogenicity of KV10.1, which need to be considered when ion channels are targeted for cancer therapy., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Kv10.1 is a voltage-gated potassium channel relevant for tumor biology, but the underlying mechanism is still unclear. We propose that Kv10.1 plays a role coordinating primary cilium disassembly with cell cycle progression through localized changes of membrane potential at the ciliary base. Most non-dividing cells display a primary cilium, an antenna-like structure important for cell physiology. The cilium is disassembled when the cell divides, which requires an increase of Ca2+ concentration and a redistribution of phospholipids in its basal region, both of which would be facilitated by local hyperpolarization. Cells lacking Kv10.1 show impaired ciliary disassembly and delayed entrance into mitosis. Kv10.1 is predominantly expressed during G2/M, a critical period for ciliary resorption, and localizes to the ciliary base and vesicles associated with the centrosome. This could explain the influence of Kv10.1 in cell proliferation, as well as phenotypic features of patients carrying gain of function mutations in the gene. [ABSTRACT FROM AUTHOR]

The primary cilium, critical for morphogenic and growth factor signaling, is assembled upon cell cycle exit, but the links between ciliogenesis and cell cycle progression are unclear. KV10.1 is a voltage-gated potassium channel frequently overexpressed in tumors. We have previously reported that expression of KV10.1 is temporally restricted to a time period immediately prior to mitosis in healthy cells. Here, we provide microscopical and biochemical evidence that KV10.1 localizes to the centrosome and the primary cilium and promotes ciliary disassembly. Interference with KV10.1 ciliary localization abolishes not only the effects on ciliary disassembly, but also KV10.1-induced tumor progression in vivo. Conversely, upon knockdown of KV10.1, ciliary disassembly is impaired, proliferation is delayed, and proliferating cells show prominent primary cilia. Thus, modulation of ciliogenesis by KV10.1 can explain the influence of KV10.1 expression on the proliferation of normal cells and is likely to be a major mechanism underlying its tumorigenic effects. [ABSTRACT FROM AUTHOR]

The electrophysiological properties of ether à go-go (EAG) potassium channels are modified during the cell cycle when they are expressed in heterologous systems. In Chinese hamster ovary (CHO) mammalian somatic cells we found that the cell-cycle-dependent modulation of human EAG (hEAG) channels occurs during the M phase. This modulation has three components: reduction in current density, increased sensitivity to block by intracellular sodium, and increased selectivity for potassium ions. In this work, these three properties have been used to define the mitotic phenotype of EAG currents. The signaling pathway leading to such changes of channel properties is unknown. We tested the hypothesis that cytoskeletal interactions might affect the electrophysiological changes observed during the cell cycle. The disruption of actin filaments induces a significant increase in current density, without inducing the cell-cycle-related phenotype. In contrast, disturbance of the microtubules, achieved by pharmacological means or by mechanical excision of the membrane patch, does induce the cell-cycle-related phenotype. Our results demonstrate that hEAG channels establish complex interactions with cytoskeletal elements, and that these interactions strongly influence the properties of the channels. We also conclude that the electrophysiological changes observed during the cell cycle are most likely due to reorganization of the cytoskeleton during the G2/M transition. [ABSTRACT FROM AUTHOR]

We have investigated the possible implication of the cell cycle-regulated K+ channel ether à go-go (EAG) in cell proliferation and transformation. We show that transfection of EAG into mammalian cells confers a transformed phenotype. In addition, human EAG mRNA is detected in several somatic cancer cell lines, despite being preferentially expressed in brain among normal tissues. Inhibition of EAG expression in several of these cancer cell lines causes a significant reduction of cell proliferation. Moreovel, the expression of EAG favours tumour progression when transfected cells are injected into immune-depressed mice. These data provide evidence for the oncogenic potential of EAG. [ABSTRACT FROM AUTHOR]