title: Regulation of IGF-1-dependent cyclin D1 and E expression by hEag1 channels in MCF-7 cells: the critical role of hEag1 channels in G1 phase progression.
abstract: Insulin-like Growth Factor-1 (IGF-1) plays a key role in breast cancer development and cell cycle regulation. It has been demonstrated that IGF-1 stimulates cyclin expression, thus regulating the G1 to S phase transition of the cell cycle. Potassium (K(+)) channels are involved in the G1 phase progression of the cell cycle induced by growth factors. However, mechanisms that allow growth factors to cooperate with K(+) channels in order to modulate the G1 phase progression and cyclin expression remain unknown. Here, we focused on hEag1 K(+) channels which are over-expressed in breast cancer and are involved in the G1 phase progression of breast cancer cells (MCF-7). As expected, IGF-1 increased cyclin D1 and E expression of MCF-7 cells in a cyclic manner, whereas the increase of CDK4 and 2 levels was sustained. IGF-1 stimulated p21(WAF1/Cip1) expression with a kinetic similar to that of cyclin D1, however p27(Kip1) expression was insensitive to IGF-1. Interestingly, astemizole, a blocker of hEag1 channels, but not E4031, a blocker of HERG channels, inhibited the expression of both cyclins after 6-8h of co-stimulation with IGF-1. However, astemizole failed to modulate CDK4, CDK2, p21(WAF1/Cip1) and p27(Kip1) expression. The down-regulation of hEag1 by siRNA provoked a decrease in cyclin expression. This study is the first to demonstrate that K(+) channels such as hEag1 are directly involved in the IGF-1-induced up-regulation of cyclin D1 and E expression in MCF-7 cells. By identifying more specifically the temporal position of the arrest site induced by the inhibition of hEag1 channels, we confirmed that hEag1 activity is predominantly upstream of the arrest site induced by serum-deprivation, prior to the up-regulation of both cyclins D1 and E. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.
authors.affiliation: Laboratoire de Physiologie Cellulaire, JE2530, Université de Picardie Jules Verne, 33 Rue St Leu, Amiens, 80039, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Borowiec
authors.forename: Frédéric
authors.initials: F
authors.lastname: Hague
authors.forename: Valérie
authors.initials: V
authors.lastname: Gouilleux-Gruart
authors.forename: Kaiss
authors.initials: K
authors.lastname: Lassoued
authors.forename: Halima
authors.initials: H
authors.lastname: Ouadid-Ahidouch
mesh_terms: D016589:Astemizole / Q000494:pharmacology; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects; D015513:Oncogene Proteins / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D016196:S Phase / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C530104:CCND1 protein, human; C475820:CCNE1 protein, human; D019927:Cyclin E; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D015513:Oncogene Proteins; D026902:Potassium Channel Blockers; D019938:Cyclin D1; D007334:Insulin-Like Growth Factor I; D016589:Astemizole