GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:21518868

From GONUTS
Jump to: navigation, search
Citation

Guo, C and Stark, GR (2011) FER tyrosine kinase (FER) overexpression mediates resistance to quinacrine through EGF-dependent activation of NF-kappaB. Proc. Natl. Acad. Sci. U.S.A. 108:7968-73

Abstract

Quinacrine, a drug with antimalarial and anticancer activities that inhibits NF-κB and activates p53, has progressed into phase II clinical trials in cancer. To further elucidate its mechanism of action and identify pathways of drug resistance, we used an unbiased method for validation-based insertional mutagenesis to isolate a quinacrine-resistant cell line in which an inserted CMV promoter drives overexpression of the FER tyrosine kinase (FER). Overexpression of FER from a cDNA confers quinacrine resistance to several different types of cancer cell lines. We show that quinacrine kills cancer cells primarily by inhibiting the activation of NF-κB and that increased activation of NF-κB through FER overexpression mediates resistance. EGF activates NF-κB and stimulates phosphorylation of FER, EGF receptor (EGFR), and ERK p42/p44, and decreased expression of FER or inhibition of ERK phosphorylation inhibits the EGF-induced activation of NF-κB. FER binds to EGFR, and overexpression of FER in cells untreated with EGF increases this association, leading to increased phosphorylation of EGFR and ERK. We conclude that FER is on a pathway connecting EGFR to NF-κB activation and that this function is responsible for FER-dependent resistance to quinacrine.

Links

PubMed PMC3093511 Online version:10.1073/pnas.1105369108

Keywords

Cell Line, Tumor; Cell Survival/physiology; Drug Resistance, Neoplasm/genetics; Drug Resistance, Neoplasm/physiology; Epidermal Growth Factor/metabolism; Gene Expression; Humans; NF-kappa B/metabolism; Proto-Oncogene Proteins c-akt/metabolism; Quinacrine/pharmacology; Receptor, Epidermal Growth Factor/metabolism; Signal Transduction; Up-Regulation

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:FER

enables

GO:0005154: epidermal growth factor receptor binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:FER

involved_in

GO:0042058: regulation of epidermal growth factor receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FER

involved_in

GO:0051092: positive regulation of NF-kappaB transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

See Help:References for how to manage references in GONUTS.