Silencing the Activity and Proliferative Properties of the Human EagI Potassium Channel by RNA Interference

Weber, Claudia; Queiroz, Fernanda Mello de; Downie, Bryan; Suckow, Arnt; Stühmer, Walter; Pardo, Luis A.

doi:10.1074/jbc.m600883200

Cited by 117 publications

(128 citation statements)

References 37 publications

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“…Recently, the Pardo's group reported siRNA sequences acting specifically on Eag1, reproducibly induced a significant decrease in the proliferation of tumor cell lines while did not trigger any observable non-specific responses [10] . So, siRNA would serve as tools in the future to facilitate the elucidation of both the physiological and pathophysiological functions of this intriguing protein.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, aberrant expression of the channel has also been detected in sarcomas [9] and other tumors from diverse origins [12] , while the surrounding tissues are devoid of Eag1 expression. Moreover, specific inhibition of Eag1 expression by antisense technique [5] , siRNA [9,10] or by non-specific blockers [7,11] leads to a reduction in tumor cell proliferation in vitro.…”

Section: Introductionmentioning

confidence: 99%

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Aberrant expression of ether à go-go potassium channel in colorectal cancer patients and cell lines

Ding¹

2007

WJG

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AIM:To study the expression of ether à go-go (Eag1) potassium channel in colorectal cancer and the relationship between their expression and clinico-pathological features. METHODS:The expression levels of Eag1 protein were determined in 76 cancer tissues with paired noncancerous matched tissues as well as 9 colorectal adenoma tissues by immunohistochemistry. Eag1 mRNA expression was detected in 13 colorectal cancer tissues with paired non-cancerous matched tissues and 4 colorectal adenoma tissues as well as two colorectal cancer cell lines (LoVo and HT-29) by reverse transcription PCR. RESULTS:The frequency of positive expression of Eag1 protein was 76.3% (58/76) and Eag1 mRNA was 76.9% (10/13) in colorectal cancer tissue. Expression level of Eag1 protein was dependent on the tumor size, lymphatic node metastasis, other organ metastases and Dukes' stage (P < 0.05), while not dependent on age, sex, site and degree of differentiation. Eag1 protein and mRNA were negative in normal colorectal tissue, and absolutely negative in colorectal adenomas except that one case was positively stained for Eag1 protein.CONCLUSION: Eag1 protein and mRNA are aberrantly expressed in colorectal cancer and occasionally expressed in colorectal adenoma. The high frequency of expression of Eag1 in tumors and the restriction of normal expression to the brain suggest the potential of this protein for diagnostic, prognostic and therapeutic purposes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Aberrant expression of ether à go-go potassium channel in colorectal cancer patients and cell lines

Ding¹

2007

WJG

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“…In summary, the expression of CNPase is associated with morpholog- ical hallmarks of remyelination at the later stages of MOG-EAE, albeit this phase is characterized by persistent redistribution of sodium channels indicating ongoing axonal injury. 40 …”

Section: Expression Of Cnpase In the Late Phase Of Mog-eae Is Associamentioning

confidence: 99%

“…RT-PCR was performed using protocols as described 40 and primers (Eurogentec S.A., Herstal, Belgium) with the following sequences: 5Ј-GGACCTTATTATGGCCCTC-AGT; GTCATTGAATATTGTGTGCCC-3Ј; and TAMRA-5Ј-AGCAGATTGCTGAATGACACCTCGGCA-3Ј-FAM.…”

Section: Rt-pcrmentioning

confidence: 99%

Re-Expression of a Developmentally Restricted Potassium Channel in Autoimmune Demyelination

Herrero-Herranz¹,

Pardo²,

Bunt³

et al. 2007

The American Journal of Pathology

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Mechanisms of lesion repair in multiple sclerosis are incompletely understood. To some degree, remyelination can occur, associated with an increase of proliferating oligodendroglial cells. Recently, the expression of potassium channels has been implicated in the control of oligodendrocyte precursor cell proliferation in vitro. We investigated the expression of Kv1.4 potassium channels in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, a model of multiple sclerosis. Confocal microscopy revealed expression of Kv1.4 in AN2-positive oligodendrocyte precursor cells and premyelinating oligodendrocytes in vitro but neither in mature oligodendrocytes nor in the spinal cords of healthy adult mice. After induction of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, Kv1.4 immunoreactivity was detected in or around lesions already during disease onset with a peak early and a subsequent decrease in the late phase of the disease. Kv1.4 expression was confined to 2,3-cyclic nucleotide 3-phosphodiesterase-positive oligodendroglial cells, which were actively proliferating and ensheathed naked axons. After a demyelinating episode, the number of Kv1.4 and 2,3-cyclic nucleotide 3-phosphodiesterase double-positive cells was greatly reduced in ciliary neurotrophic factor knockout mice, a model with impaired lesion repair. In summary, the re-expression of an oligodendroglial potassium channel may have a functional implication on oligodendroglial cell cycle progression, thus influencing tissue repair in experimental autoimmune encephalomyelitis and multiple sclerosis.

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“…The voltage-gated potassium channel ether-à -go-go (eag), first identified in Drosophila melanogaster based on the legshaking mutant phenotype (Kaplan and Trout 1969;Warmke et al 1991), has mammalian homologs that fall into three subfamilies-EAG (EAG1 and EAG2), EAGlike (ELK1, ELK2, and ELK3), and EAG-related (ERG1, ERG2, and ERG3)-which are voltage-gated potassium channels with distinct electrophysiological properties (Ganetzky et al 1999). 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.…”

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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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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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Silencing the Activity and Proliferative Properties of the Human EagI Potassium Channel by RNA Interference

Cited by 117 publications

References 37 publications

Aberrant expression of ether à go-go potassium channel in colorectal cancer patients and cell lines

Aberrant expression of ether à go-go potassium channel in colorectal cancer patients and cell lines

Re-Expression of a Developmentally Restricted Potassium Channel in Autoimmune Demyelination

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

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