Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells
Journal
RNA
Journal Volume
22
Journal Issue
2
Pages
303-315
Date Issued
2016
Author(s)
Cho C.-Y.
Huang J.-S.
Shiah S.-G.
Chung S.-Y.
Lay J.-D.
Yang Y.-Y.
Lai G.-M.
Chen L.-T.
Chuang S.-E.
Abstract
The AXL receptor tyrosine kinase is frequently overexpressed in cancers and is important in cancer invasion/metastasis and chemoresistance. Here, we demonstrate a regulatory feedback loop between AXL and microRNA (miRNA) at the posttranscriptional level. Both the GAS6-binding domain and the kinase domain of AXL, particularly the Y779 tyrosine phosphorylation site, are shown to be crucial for this autoregulation. To clarify the role of miRNAs in this regulation loop, approaches using bioinformatics and molecular techniques were applied, revealing that miR-34a may target the 3' UTR of AXL mRNA to inhibit AXL expression. Interestingly and importantly, AXL overexpression may induce miR-34a expression by activating the transcription factor ELK1 via the JNK signaling pathway. In addition, ectopic overexpression of ELK1 promotes apoptosis through, in part, down-regulation of AXL. Therefore, we propose that AXL is autoregulated by miR-34a in a feedback loop; this may provide a novel opportunity for developing AXL-targeted anticancer therapies. ? 2016 Cho et al.
Subjects
Apoptosis; AXL; ELK1; Feedback loop regulation; JNK; MiR-34a
SDGs
Other Subjects
axl protein tyrosine kinase; messenger RNA; microRNA 34a; protein tyrosine kinase; stress activated protein kinase; transcription factor Elk 1; unclassified drug; axl receptor tyrosine kinase; ELK1 protein, human; microRNA; MIRN34 microRNA, human; mitogen activated protein kinase kinase 4; oncoprotein; protein binding; protein tyrosine kinase; transcription factor Elk 1; tyrosine; 3' untranslated region; apoptosis; Article; autophosphorylation; autoregulation; bioinformatics; down regulation; human; human cell; lung cancer; negative feedback; priority journal; protein binding; protein expression; protein phosphorylation; apoptosis; binding site; epithelium cell; gene expression regulation; genetics; lung; metabolism; microarray analysis; pathology; phosphorylation; physiological feedback; signal transduction; tumor cell line; Apoptosis; Binding Sites; Cell Line, Tumor; Epithelial Cells; ets-Domain Protein Elk-1; Feedback, Physiological; Gene Expression Regulation, Neoplastic; Humans; Lung; MAP Kinase Kinase 4; Microarray Analysis; MicroRNAs; Phosphorylation; Protein Binding; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Signal Transduction; Tyrosine
Publisher
Cold Spring Harbor Laboratory Press
Type
journal article