title: Critical role of phosphorylation of serine 165 of YBX1 on the activation of NF-κB in colon cancer.
abstract: Y-box binding protein 1 [YBX1] is a multifunctional protein known to facilitate many of the hallmarks of cancer. Elevated levels of YBX1 protein are highly correlated with cancer progression, making it an excellent marker in cancer. The connection between YBX1 and the important nuclear factor κB [NF-κB] has never been reported. Here, we show that overexpression of wild type YBX1 [WT-YBX1] activates NF-κB, suggesting that YBX1 is a potential NF-κB activator. Furthermore, using mass spectrometry analysis we identified novel phosphorylation of serine 165 [S165] on YBX1. Overexpression of the S165A-YBX1 mutant in either HEK293 cells or colon cancer HT29 cells showed dramatically reduced NF-κB activating ability as compared with that of WT-YBX1, confirming that S165 phosphorylation is critical for the activation of NF-κB by YBX1. We also show that expression of the S165A-YBX1 mutant dramatically decreased the expression of NF-κB-inducible genes, reduced cell growth, and compromised tumorigenic ability as compared with WT-YBX1. Taken together, we provide the first evidence that YBX1 functions as a tumor promoter via NF-κB activation, and phosphorylation of S165 of YBX1 is critical for this function. Therefore, our important discovery may lead to blocking S165 phosphorylation as a potential therapeutic strategy to treat colon cancer.
authors: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: Lakshmi
authors: L
authors: Prabhu
authors: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: Rasika
authors: R
authors: Mundade
authors: Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Benlian
authors: B
authors: Wang
authors: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: Han
authors: H
authors: Wei
authors: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: Antja-Voy
authors: AV
authors: Hartley
authors: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: Matthew
authors: M
authors: Martin
authors: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: Kyle
authors: K
authors: McElyea
authors: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: Constance J
authors: CJ
authors: Temm
authors: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: George
authors: G
authors: Sandusky
authors: Department of Medical and Molecular Genetics, Medical Research and Library Building, Indianapolis, IN, USA.|Center for Computational Biology and Bioinformatics, Health Information and Translational Sciences, Indianapolis, IN, USA.
authors: Yunlong
authors: Y
authors: Liu
authors: Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.|Department of Medical and Molecular Genetics, Medical Research and Library Building, Indianapolis, IN, USA.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: Tao
authors: T
authors: Lu
mesh_terms: D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation; D012694:Serine; D015398:Signal Transduction; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D051840:Y-Box-Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; C498143:RELA protein, human; D051996:Transcription Factor RelA; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D000072000:NF-KappaB Inhibitor alpha; D012694:Serine
keywords: NF-κB; YBX1; colon cancer; phosphorylation; serine