Abstract
The FRA-1 proto-oncogene is overexpressed in a variety of human tumors and is known to up-regulate the expression of genes involved in tumor progression and invasion. The phosphatidylinositol 3-kinase (PI3K)-Akt pathway is also known to regulate these cellular processes. More importantly, respiratory toxicants and carcinogens activate both the PI3K-Akt pathway and FRA-1 expression in human bronchial epithelial (HBE) cells. In this study we investigated a potential link between the PI3K-Akt pathway and the cigarette smoke (CS)-stimulated epidermal growth factor receptor-mediated FRA-1 induction in non-oncogenic HBE cells. Treatment of cells with LY294002, an inhibitor of the PI3K-Akt pathway, completely blocked CS-induced FRA-1 expression. Surprisingly pharmacological inhibition of Akt had no significant effect on CS-induced FRA-1 expression. Likewise the inhibition of protein kinase C zeta, which is a known downstream effector of PI3K, did not alter FRA-1 expression. We found that the PI3K through p21-activated kinase 1 regulates FRA-1 proto-oncogene induction by CS and the subsequent activation of the Elk1 and cAMP-response element-binding protein transcription factors that are bound to the promoter in HBE cells.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Carcinogens / pharmacology
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Cell Line
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Chromatin Immunoprecipitation
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Chromones / pharmacology
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Cyclic AMP Response Element-Binding Protein / metabolism
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DNA / metabolism
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ErbB Receptors / metabolism
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Gene Expression Regulation
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Gene Expression Regulation, Enzymologic*
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Genetic Vectors
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Humans
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Immunoblotting
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Immunoprecipitation
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Models, Biological
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Models, Genetic
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Morpholines / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism*
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Plasmids / metabolism
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Promoter Regions, Genetic
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Mas
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Proto-Oncogene Proteins c-akt / metabolism*
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Proto-Oncogene Proteins c-akt / physiology*
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Proto-Oncogene Proteins c-fos / metabolism*
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Proto-Oncogene Proteins c-raf / metabolism
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RNA, Messenger / metabolism
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Signal Transduction
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Smoking
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Time Factors
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Transcription, Genetic
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Transfection
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ets-Domain Protein Elk-1 / metabolism*
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p21-Activated Kinases
Substances
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Carcinogens
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Chromones
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Cyclic AMP Response Element-Binding Protein
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MAS1 protein, human
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Morpholines
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Proto-Oncogene Mas
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Proto-Oncogene Proteins c-fos
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RNA, Messenger
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ets-Domain Protein Elk-1
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fos-related antigen 1
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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DNA
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ErbB Receptors
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PAK1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-raf
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p21-Activated Kinases