國家衛生研究院 NHRI:Item 3990099045/5495
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    題名: Epidermal growth factor receptor mutation in combination with expression of MIG6 alters gefitinib sensitivity
    作者: Naruo, Y;Nagashima, T;Ushikoshi-Nakayama, R;Saeki, Y;Nakakuki, T;Naka, T;Tanaka, H;Tsai, SF;Okada-Hatakeyama, M
    貢獻者: Division of Molecular and Genomic Medicine
    摘要: Background: Epidermal growth factor receptor (EGFR) signaling plays an important role in the regulation of cell proliferation, survival, metastasis, and invasion in various tumors. Earlier studies showed that the EGFR is frequently overexpressed in non-small-cell lung cancer (NSCLC) and EGFR mutations at specific amino acid residues in the kinase domain induce altered responsiveness to gefitinib, a small molecule EGFR tyrosine kinase inhibitor. However, the mechanism underlying the drug response modulated by EGFR mutation is still largely unknown. To elucidate drug response in EGFR signal transduction pathway in which complex dynamics of multiple molecules involved, a systematic approach is necessary. In this paper, we performed experimental and computational analyses to clarify the underlying mechanism of EGFR signaling and cell-specific gefitinib responsiveness in three H1299-derived NSCLC cell lines; H1299 wild type (H1299WT), H1299 with an overexpressed wild type EGFR (H1299EGFR-WT), and H1299 with an overexpressed mutant EGFR L858R (H1299L858R; gefitinib sensitive mutant).Results: We predicted and experimentally verified that Mig6, which is a known negative regulator of EGFR and specifically expressed in H1299L858R cells, synergized with gefitinib to suppress cellular growth. Computational analyses indicated that this inhibitory effect is amplified at the phosphorylation/dephosphorylation steps of MEK and ERK.Conclusions: Thus, we showed that L858R receptor mutation in combination with expression of its negative regulator, Mig6, alters signaling outcomes and results in variable drug sensitivity.
    日期: 2011-02-18
    關聯: BMC Systems Biology. 2011 Feb 18;5:Article number 29.
    Link to: http://dx.doi.org/10.1186/1752-0509-5-29
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000291874800001
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=79951563038
    顯示於類別:[蔡世峯] 期刊論文

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