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Received for publication September 26, 2005.
Revised December 31, 2005.
Accepted for publication January 4, 2006.
Epidermal growth factor (EGF) is a multifunctional growth factor known to play a major role in proliferation and differentiation processes. EGF-induced differentiation is a prerequisite for function of various cell types, among them cytotrophoblasts, a functionally important cellular fraction in human placenta. Stimulation of cytotrophoblasts with EGF results in formation of a multinuclear syncytium representing the feto-maternal interface, which protects the fetus against exogenous substances. It is well established, that part of this protection system is based on ABC transporters such as ABCG2 (Breast Cancer Resistance Protein/BCRP). However, little is known about regulation of transport proteins in the framework of EGF-mediated cellular differentiation. In the present work we show a significant increase of ABCG2-expression by EGF in cytotrophoblasts, BeWo and MCF-7 cells on both mRNA and protein levels. This increase resulted in decreased sensitivity to the ABCG2 substrates mitoxantrone and topotecan. In each cell type EGF increases expression of ABCG2 by activation of MAPK cascade via phosphorylation of ERK1/2 and JNK/SAPK. Consequently, the increase of ABCG2 by EGF was abolished by pre-treatment of cells with the tyrosine kinase inhibitor AG1478 or the MEK inhibitor PD 98059, thereby re-establishing sensitivity towards mitoxantrone. Moreover, analysis of ABCG2 expression during placental development revealed a significant increase in preterm versus term placenta. Taken together, our data show regulation of ABCG2 expression by EGF. In view of EGF signal transduction as a target for drugs (e.g. gefitinib), which are in turn substrates and/or inhibitors of ABCG2, this regulation has therapeutic consequences.
Key words:
ABC transporters, membrane barriers, multi-drug resistance, transporters
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