Abstract
Epidermal growth factor receptor (EGFR) exists in the nucleus of highly proliferative cells where it functions as a transcription factor. Although EGFR has transactivational activity, it lacks a DNA binding domain and, therefore, may require a DNA binding transcription cofactor for its transcriptional function. Here, we report that EGFR physically interacts with signal transducers and activators of transcription 3 (STAT3) in the nucleus, leading to transcriptional activation of inducible nitric oxide synthase (iNOS). In breast carcinomas, nuclear EGFR positively correlates with iNOS. This study describes a mode of transcriptional control involving cooperated efforts of STAT3 and nuclear EGFR. Our work suggests that the deregulated iNOS/NO pathway may partly contribute to the malignant biology of tumor cells with high levels of nuclear EGFR and STAT3.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Base Sequence
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Binding Sites / genetics
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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CHO Cells
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Cell Line, Tumor
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism*
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Cell Nucleus / ultrastructure
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Cell Survival / drug effects
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Chromatin Immunoprecipitation
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Cricetinae
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Cricetulus
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DNA-Binding Proteins / metabolism*
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Drug Synergism
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Epidermal Growth Factor / pharmacology
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / metabolism*
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Female
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Gene Expression / drug effects
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Gene Expression Regulation, Neoplastic
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Genes, bcl-1 / genetics
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Genes, fos / genetics
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HeLa Cells
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Humans
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Janus Kinase 2
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Microscopy, Fluorescence
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Microscopy, Immunoelectron
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Nitric Oxide / metabolism
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Nitric Oxide / physiology*
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Nitric Oxide Synthase / antagonists & inhibitors
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase / metabolism*
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Nitric Oxide Synthase Type II
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Phosphorylation / drug effects
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Prognosis
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Promoter Regions, Genetic / genetics
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Protein Binding / drug effects
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Protein Kinase Inhibitors / pharmacology
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Proto-Oncogene Proteins / antagonists & inhibitors
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S-Nitroso-N-Acetylpenicillamine / pharmacology
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STAT3 Transcription Factor
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Signal Transduction / drug effects
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Survival Analysis
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Trans-Activators / metabolism*
Substances
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DNA-Binding Proteins
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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STAT3 Transcription Factor
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STAT3 protein, human
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Trans-Activators
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Nitric Oxide
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Epidermal Growth Factor
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S-Nitroso-N-Acetylpenicillamine
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NOS2 protein, human
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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ErbB Receptors
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Protein-Tyrosine Kinases
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JAK2 protein, human
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Janus Kinase 2