期刊
SCIENCE SIGNALING
卷 8, 期 375, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2005978
关键词
-
资金
- Howard Hughes Medical Institute
- NIH [CA104838]
Receptor tyrosine kinase (RTK) signaling promotes the growth and progression of glioblastoma (GBM), a highly aggressive type of brain tumor. We previously reported that decreased miR-218 expression in GBM directly promotes RTK activity by increasing the expression of key RTKs and their signaling mediators, including the RTK epidermal growth factor receptor (EGFR), phospholipase C-gamma 1 (PLC gamma 1), and the kinases PIK3CA and ARAF. However, increased RTK signaling usually activates negative feedback mechanisms to maintain homeostasis. We found that decreased miR-218 expression in GBM cells also increased the expression of genes encoding additional upstream and downstream components of RTK signaling pathways, including the RTK platelet-derived growth factor receptor alpha (PDGFR alpha) and the kinases ribosomal S6 kinase 2 (RSK2) and S6 kinase 1 (S6K1), that collectively overrode the negative feedback mechanism. Furthermore, increased RTK signaling itself suppressed miR-218 expression. Mass spectrometry and DNA pull-down identified binding of signal transducer and activator of transcription 3 (STAT3) along with the transcriptional repressor BCL2-associated transcription factor 1 (BCLAF1) directly to the miR-218 locus. These data identify previously unknown feedback loops by which miR-218 repression promotes increased RTK signaling in high-grade gliomas.
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