Identification of a posttranslational mechanism for the regulation of hERG1 K+ channel expression and hERG1 current density in tumor cells.
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.
Department of Experimental Pathology and Oncology, University of Florence, Viale G. B. Morgagni 50, 50134 Florence, Italy.
Leonardo
L
Guasti
Olivia
O
Crociani
Elisa
E
Redaelli
Serena
S
Pillozzi
Simone
S
Polvani
Marika
M
Masselli
Tommaso
T
Mello
Andrea
A
Galli
Amedeo
A
Amedei
Randy S
RS
Wymore
Enzo
E
Wanke
Annarosa
A
Arcangeli
D017398:Alternative Splicing / Q000235:genetics; D017209:Apoptosis; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006262:Health; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D015640:Ion Channel Gating; D008954:Models, Biological; D008969:Molecular Sequence Data; D016501:Neurites / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D018076:DNA, Complementary; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D020033:Protein Isoforms; D012333:RNA, Messenger