Identification of a posttranslational mechanism for the regulation of hERG1 K+ channel expression and hERG1 current density in tumor cells

Leonardo Guasti, Olivia Crociani, Elisa Redaelli, Serena Pillozzi, Simone Polvani, Marika Masselli, Tommaso Mello, Andrea Galli, Amedeo Amedei, Randy Wymore, Enzo Wanke, Annarosa Arcangeli

Research output: Contribution to journalArticle

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Abstract

A common feature of tumor cells is the aberrant expression of ion channels on their plasma membrane. The molecular mechanisms regulating ion channel expression in cancer cells are still poorly known. K+ channels that belong to the human ether-a-go-go-related gene 1 (herg1) family are frequently misexpressed in cancer cells compared to their healthy counterparts. We describe here a posttranslational mechanism for the regulation of hERG1 channel surface expression in cancer cells. This mechanism is based on the activity of hERG1 isoforms containing the USO exon. These isoforms (i) are frequently overexpressed in human cancers, (ii) are retained in the endoplasmic reticulum, and (iii) form heterotetramers with different proteins of the hERG family. (iv) The USO-containing heterotetramers are retained intracellularly and undergo ubiquitin-dependent degradation. This process results in decreased hERG1 current (IhERG1) density. We detailed such a mechanism in heterologous systems and confirmed its functioning in tumor cells that endogenously express hERG1 proteins. The silencing of USO-containing hERG1 isoforms induces a higher IhERG1 density in tumors, an effect that apparently regulates neurite outgrowth in neuroblastoma cells and apoptosis in leukemia cells.

Original languageEnglish
Pages (from-to)5043-5060
Number of pages18
JournalMolecular and Cellular Biology
Volume28
Issue number16
DOIs
StatePublished - 1 Aug 2008

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Neoplasms
Protein Isoforms
Ion Channels
Ubiquitin
Neuroblastoma
Endoplasmic Reticulum
Ether
Exons
Leukemia
Proteins
Cell Membrane
Apoptosis
Genes

Cite this

Guasti, Leonardo ; Crociani, Olivia ; Redaelli, Elisa ; Pillozzi, Serena ; Polvani, Simone ; Masselli, Marika ; Mello, Tommaso ; Galli, Andrea ; Amedei, Amedeo ; Wymore, Randy ; Wanke, Enzo ; Arcangeli, Annarosa. / Identification of a posttranslational mechanism for the regulation of hERG1 K+ channel expression and hERG1 current density in tumor cells. In: Molecular and Cellular Biology. 2008 ; Vol. 28, No. 16. pp. 5043-5060.
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abstract = "A common feature of tumor cells is the aberrant expression of ion channels on their plasma membrane. The molecular mechanisms regulating ion channel expression in cancer cells are still poorly known. K+ channels that belong to the human ether-a-go-go-related gene 1 (herg1) family are frequently misexpressed in cancer cells compared to their healthy counterparts. We describe here a posttranslational mechanism for the regulation of hERG1 channel surface expression in cancer cells. This mechanism is based on the activity of hERG1 isoforms containing the USO exon. These isoforms (i) are frequently overexpressed in human cancers, (ii) are retained in the endoplasmic reticulum, and (iii) form heterotetramers with different proteins of the hERG family. (iv) The USO-containing heterotetramers are retained intracellularly and undergo ubiquitin-dependent degradation. This process results in decreased hERG1 current (IhERG1) density. We detailed such a mechanism in heterologous systems and confirmed its functioning in tumor cells that endogenously express hERG1 proteins. The silencing of USO-containing hERG1 isoforms induces a higher IhERG1 density in tumors, an effect that apparently regulates neurite outgrowth in neuroblastoma cells and apoptosis in leukemia cells.",
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Guasti, L, Crociani, O, Redaelli, E, Pillozzi, S, Polvani, S, Masselli, M, Mello, T, Galli, A, Amedei, A, Wymore, R, Wanke, E & Arcangeli, A 2008, 'Identification of a posttranslational mechanism for the regulation of hERG1 K+ channel expression and hERG1 current density in tumor cells', Molecular and Cellular Biology, vol. 28, no. 16, pp. 5043-5060. https://doi.org/10.1128/MCB.00304-08

Identification of a posttranslational mechanism for the regulation of hERG1 K+ channel expression and hERG1 current density in tumor cells. / Guasti, Leonardo; Crociani, Olivia; Redaelli, Elisa; Pillozzi, Serena; Polvani, Simone; Masselli, Marika; Mello, Tommaso; Galli, Andrea; Amedei, Amedeo; Wymore, Randy; Wanke, Enzo; Arcangeli, Annarosa.

In: Molecular and Cellular Biology, Vol. 28, No. 16, 01.08.2008, p. 5043-5060.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of a posttranslational mechanism for the regulation of hERG1 K+ channel expression and hERG1 current density in tumor cells

AU - Guasti, Leonardo

AU - Crociani, Olivia

AU - Redaelli, Elisa

AU - Pillozzi, Serena

AU - Polvani, Simone

AU - Masselli, Marika

AU - Mello, Tommaso

AU - Galli, Andrea

AU - Amedei, Amedeo

AU - Wymore, Randy

AU - Wanke, Enzo

AU - Arcangeli, Annarosa

PY - 2008/8/1

Y1 - 2008/8/1

N2 - A common feature of tumor cells is the aberrant expression of ion channels on their plasma membrane. The molecular mechanisms regulating ion channel expression in cancer cells are still poorly known. K+ channels that belong to the human ether-a-go-go-related gene 1 (herg1) family are frequently misexpressed in cancer cells compared to their healthy counterparts. We describe here a posttranslational mechanism for the regulation of hERG1 channel surface expression in cancer cells. This mechanism is based on the activity of hERG1 isoforms containing the USO exon. These isoforms (i) are frequently overexpressed in human cancers, (ii) are retained in the endoplasmic reticulum, and (iii) form heterotetramers with different proteins of the hERG family. (iv) The USO-containing heterotetramers are retained intracellularly and undergo ubiquitin-dependent degradation. This process results in decreased hERG1 current (IhERG1) density. We detailed such a mechanism in heterologous systems and confirmed its functioning in tumor cells that endogenously express hERG1 proteins. The silencing of USO-containing hERG1 isoforms induces a higher IhERG1 density in tumors, an effect that apparently regulates neurite outgrowth in neuroblastoma cells and apoptosis in leukemia cells.

AB - A common feature of tumor cells is the aberrant expression of ion channels on their plasma membrane. The molecular mechanisms regulating ion channel expression in cancer cells are still poorly known. K+ channels that belong to the human ether-a-go-go-related gene 1 (herg1) family are frequently misexpressed in cancer cells compared to their healthy counterparts. We describe here a posttranslational mechanism for the regulation of hERG1 channel surface expression in cancer cells. This mechanism is based on the activity of hERG1 isoforms containing the USO exon. These isoforms (i) are frequently overexpressed in human cancers, (ii) are retained in the endoplasmic reticulum, and (iii) form heterotetramers with different proteins of the hERG family. (iv) The USO-containing heterotetramers are retained intracellularly and undergo ubiquitin-dependent degradation. This process results in decreased hERG1 current (IhERG1) density. We detailed such a mechanism in heterologous systems and confirmed its functioning in tumor cells that endogenously express hERG1 proteins. The silencing of USO-containing hERG1 isoforms induces a higher IhERG1 density in tumors, an effect that apparently regulates neurite outgrowth in neuroblastoma cells and apoptosis in leukemia cells.

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U2 - 10.1128/MCB.00304-08

DO - 10.1128/MCB.00304-08

M3 - Article

C2 - 18559421

AN - SCOPUS:49449109702

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SN - 0270-7306

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