Cell Cycle-dependent Expression of HERG1 and HERG1B Isoforms in Tumor Cells

Olivia Crociani,Leonardo Guasti,Manuela Balzi,Andrea Becchetti,Enzo Wanke,Massimo Olivotto,Randy S Wymore,Annarosa Arcangeli

doi:10.1074/jbc.m210789200

Olivia Crociani, Leonardo Guasti + Show 6 more

Open Access

https://doi.org/10.1074/jbc.m210789200

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Abstract

The role of K(+) channel activity during cell cycle progression has become a research topic of considerable interest. Blocking of K(+) channels inhibits the proliferation of many cell types, although the mechanism of this inhibition is unclear. There is speculation that K(+) channels differentially regulate the electrical potential of the plasma membrane (V(m)) during proliferation. We have demonstrated that in tumor cells the value of V(m) is clamped to rather depolarized values by K(+) channels belonging to the HERG family. We report here that tumor cell lines preferentially express the herg1 gene and a truncated, N-deleted form that corresponds to herg1b. This alternative transcript is also expressed in human primary acute myeloid leukemias. Both HERG1 and HERG1B proteins are expressed on the plasma membrane of tumor cells and can form heterotetramers. The expression of HERG protein isoforms is strongly cell cycle-dependent, accounting for variations in HERG currents along the mitotic cycle. Moreover, the blocking of HERG channels dramatically impairs cell growth of HERG-bearing tumor cells. These results suggest that modulated expression of different K(+) channels is the molecular basis of a novel mechanism regulating neoplastic cell proliferation.

Highlights

Availability: This version is available at: 2158/312239 since: Terms of use: Open Access La pubblicazione è resa disponibile sotto le norme e i termini della licenza di deposito, secondo quanto stabilito dalla Policy per l'accesso aperto dell'Università degli Studi di Firenze
Human brain RNA was used as a control for herg1 and herg3, whereas RNA from human retinoblastoma Y-79 cells was used as a control for herg2 expression
Results reported in this paper clearly show that various tumor cell lines preferentially express the herg1 gene along with a truncated form of the HERG1 protein that corresponds to the alternative transcript of herg1 first discovered in the heart, herg1b

Summary

Introduction

Availability: This version is available at: 2158/312239 since: Terms of use: Open Access La pubblicazione è resa disponibile sotto le norme e i termini della licenza di deposito, secondo quanto stabilito dalla Policy per l'accesso aperto dell'Università degli Studi di Firenze (https://www.sba.unifi.it/upload/policy-oa-2016-1.pdf). We report here that tumor cell lines preferentially express the herg gene and a truncated, N-deleted form that corresponds to herg1b. This alternative transcript is expressed in human primary acute myeloid leukemias. Both HERG1 and HERG1B proteins are expressed on the plasma membrane of tumor cells and can form heterotetramers. The blocking of HERG channels dramatically impairs cell growth of HERG-bearing tumor cells. These results suggest that modulated expression of different K؉ channels is the molecular basis of a novel mechanism regulating neoplastic cell proliferation. The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AJ512214

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