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Molecular and Cellular Biology, August 2008, p. 5043-5060, Vol. 28, No. 16
0270-7306/08/$08.00+0     doi:10.1128/MCB.00304-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Identification of a Posttranslational Mechanism for the Regulation of hERG1 K⁺ Channel Expression and hERG1 Current Density in Tumor Cells

Leonardo Guasti,^1, Olivia Crociani,^1, Elisa Redaelli,² Serena Pillozzi,¹ Simone Polvani,³ Marika Masselli,¹ Tommaso Mello,⁴ Andrea Galli,⁴ Amedeo Amedei,⁵ Randy S. Wymore,⁶ Enzo Wanke,² and Annarosa Arcangeli^1*

Department of Experimental Pathology and Oncology, University of Florence, Viale G. B. Morgagni 50, 50134 Florence, Italy,¹ Department of Biotechnology and Biosciences, University of Milan-Bicocca, Piazza delle Scienze 2, Milan 20126, Italy,² FiorGen Farmacogenomic Foundation, Via Luigi Sacconi 6, 50019 Sesto Fiorentino, Florence, Italy,³ Gastroenterology Unit, Department of Clinical Pathophysiology, University of Florence, Viale Pieraccini 6, 50134 Florence, Italy,⁴ Department of Internal Medicine, University of Florence, Viale Pieraccini 6, 50134 Florence, Italy,⁵ Oklahoma State University-Center for Health Sciences, Tulsa, Oklahoma 74104⁶

Received 22 February 2008/ Returned for modification 25 March 2008/ Accepted 4 June 2008

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 (I_hERG1) 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 I_hERG1 density in tumors, an effect that apparently regulates neurite outgrowth in neuroblastoma cells and apoptosis in leukemia cells.

Published ahead of print on 16 June 2008.

These two authors equally contributed to the paper.