Overexpression of Eag1 potassium channels in clinical tumours

Hemmerlein, Bernhard; Weseloh, Rüdiger; Queiroz, Fernanda Mello de; Knötgen, Hendrik; Sánchez, Araceli; Rubio, María E.; Martin, Sabine; Schliephacke, Tessa geb. Elbert; Jenke, Marc; Heinz-Joachim-Radzun,; Stühmer, Walter; Pardo, Luis A.

doi:10.1186/1476-4598-5-41

Cited by 229 publications

(201 citation statements)

References 48 publications

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“…Selective up-regulation of HERG in several human neoplasms, but not their normal tissue counterparts, has been reported, and pharmacological inhibition of the HERG channel is efficacious in reducing tumor cell proliferation in primary leukemic cells (Pillozzi et al 2002;Jehle et al 2011). Aberrant EAG1 expression has been reported in >75% of human tumors, and its inhibition decreases the proliferation of EAG1-expressing cells (Pardo et al 2005;Hemmerlein et al 2006;Mello de Queiroz et al 2006). While potassium channels have been implicated in cancer, little is known about how ion channels regulate tumor growth and progression.…”

Section: Discussionmentioning

confidence: 99%

“…EAG1 (KCNH1, Kv10.1) has been studied for its potential role in cancer (Pardo et al 1999(Pardo et al , 2005Weber et al 2006). While its normal expression is largely confined to the CNS, EAG1 is highly expressed in >75% of human non-CNS cancers (Hemmerlein et al 2006;Mello de Queiroz et al 2006), although the mechanism by which EAG1 stimulates tumor growth is unknown. It is also unknown whether EAG2 (KCNH5, Kv10.2), which displays much higher expression in the cerebral cortex than the cerebellum (Ludwig et al 2000), has any involvement in cancer.…”

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confidence: 99%

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Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

et al. 2012

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Medulloblastoma (MB) is the most common pediatric CNS malignancy. We identify EAG2 as an overexpressed potassium channel in MBs across different molecular and histological subgroups. EAG2 knockdown not only impairs MB cell growth in vitro, but also reduces tumor burden in vivo and enhances survival in xenograft studies. Mechanistically, we demonstrate that EAG2 protein is confined intracellularly during interphase but is enriched in the plasma membrane during late G2 phase and mitosis. Disruption of EAG2 expression results in G2 arrest and mitotic catastrophe associated with failure of premitotic cytoplasmic condensation. While the tumor suppression function of EAG2 knockdown is independent of p53 activation, DNA damage checkpoint activation, or changes in the AKT pathway, this defective cell volume control is specifically associated with hyperactivation of the p38 MAPK pathway. Inhibition of the p38 pathway significantly rescues the growth defect and G2 arrest. Strikingly, ectopic membrane expression of EAG2 in cells at interphase results in cell volume reduction and mitotic-like morphology. Our study establishes the functional significance of EAG2 in promoting MB tumor progression via regulating cell volume dynamics, the perturbation of which activates the tumor suppressor p38 MAPK pathway, and provides clinical relevance for targeting this ion channel in human MBs.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

et al. 2012

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“…hEag1 has also been correlated to processes like cell-cycle and proliferation, and appears to be implicated in tumour progression in up to 75% of solid tumours. (Bauer and Schwarz 2001;Hemmerlein et al 2006;Pardo 2004). In contrast, hEag2, besides being ubiquitous, does not have the oncogenic potential of hEag1.…”

Section: Introductionmentioning

confidence: 96%

The voltage dependence of hEag currents is not determined solely by membrane-spanning domains

et al. 2008

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The ether-à-go-go potassium channels hEag1 and hEag2 are highly homologous. Even though both possess identical voltage-sensing domain S4, the channels act differently in response to voltage. Therefore we asked whether transmembrane domains other than the voltage sensor could contribute to the voltage-dependent behaviour of these potassium channels. For this chimaeras were created, in which each single transmembrane domain of hEag1 was replaced by the corresponding segment of hEag2. The voltage-dependent properties of the chimaeras were analysed after expression in Xenopus laevis oocytes using the two-electrode voltage-clamp method. By this we found, that only the mutations in transmembrane domains S5 and S6 are able to change the voltage sensitivity of hEag1 by shifting the half-activation potential (V 50 ) to values intermediate between the two wild types. Moreover, the presence of Mg 2+ has strong effects on the voltage sensitivity of hEag2 shifting V 50 by more than 50 mV to more positive values. Interestingly, despite the identical binding site Mg 2+ showed only little effects on hEag1 or the chimaeras. Altogether, our data suggest that not only transmembrane spanning regions, but also non-membrane spanning regions are responsible for differences in the behaviour of the hEag1 and hEag2 potassium channels.

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“…In addition, these channels are up-regulated by oestrogens and human papilloma virus (HPV) oncogenes (Díaz et al 2009) and have been reported in almost 50% of patients taking oestrogens (Ortiz et al 2011). Distribution of KCNH1 in normal human tissues is mainly restricted to the brain, myoblasts and adrenal gland and to the reproductionassociated organs placenta and testes (Occhiodoro et al 1998, Pardo et al 1999, Hemmerlein et al 2006, Díaz et al 2009). Nevertheless, the precise role of KCNH1 in normal tissues is nearly unknown.…”

Section: Introductionmentioning

confidence: 99%

KCNH1 potassium channels are expressed in cervical cytologies from pregnant patients and are regulated by progesterone

et al. 2013

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Potassium voltage-gated channel, subfamily H (eag-related), member 1 (KCNH1) potassium channels are potential tumour markers and cancer therapeutic targets and are up-regulated by oestrogens and human papilloma virus (HPV) oncogenes. However, the role of KCNH1 in normal tissues is poorly understood, and its expression in pregnancy is unknown. We wondered whether KCNH1 channels are expressed in cervical cells from pregnant patients and whether progesterone (P 4 ) regulates KCNH1. The association with HPV was also investigated. KCNH1 protein expression was studied by immunocytochemistry in liquid-based cervical cytologies; 93 samples were obtained from pregnant patients at different trimesters, and 15 samples were obtained from non-pregnant women (controls). The presence of HPV was studied by PCR with direct sequencing and nested multiplex PCR. HeLa cervical cancer cells were transfected with human progesterone receptor-B (PR-B) and treated with P 4 . KCNH1 mRNA expression in these cultures was studied by real-time PCR. KCNH1 protein was detected in 100% of the pregnancy samples and in 26% of the controls. We found 18 pregnant patients infected with HPV and detected 14 types of HPV. There was no association between the percentage of cells expressing KCNH1 and either the presence or type of HPV. P 4 induced KCNH1 mRNA and protein expression in cells transfected with human PR-B. No regulation of KCNH1 by P 4 was observed in non-transfected cells. We show for the first time the expression of an ion channel during human pregnancy at different trimesters and KCNH1 regulation by P 4 in human cells. These data raise a new research field for KCNH1 channels in human tissues.

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Overexpression of Eag1 potassium channels in clinical tumours

Cited by 229 publications

References 48 publications

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

The voltage dependence of hEag currents is not determined solely by membrane-spanning domains

KCNH1 potassium channels are expressed in cervical cytologies from pregnant patients and are regulated by progesterone

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