A Phosphatidylinositol 3-kinase-regulated Akt-independent signaling promotes cigarette smoke-induced FRA-1 expression

J Biol Chem. 2006 Apr 14;281(15):10174-81. doi: 10.1074/jbc.M513008200. Epub 2006 Feb 20.

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

  • Research Support, N.I.H., Extramural

MeSH terms

  • Carcinogens / pharmacology
  • Cell Line
  • Chromatin Immunoprecipitation
  • Chromones / pharmacology
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • DNA / metabolism
  • ErbB Receptors / metabolism
  • Gene Expression Regulation
  • Gene Expression Regulation, Enzymologic*
  • Genetic Vectors
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Models, Biological
  • Models, Genetic
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Plasmids / metabolism
  • Promoter Regions, Genetic
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Proto-Oncogene Proteins c-akt / physiology*
  • Proto-Oncogene Proteins c-fos / metabolism*
  • Proto-Oncogene Proteins c-raf / metabolism
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Smoking
  • Time Factors
  • Transcription, Genetic
  • Transfection
  • ets-Domain Protein Elk-1 / metabolism*
  • p21-Activated Kinases

Substances

  • Carcinogens
  • Chromones
  • Cyclic AMP Response Element-Binding Protein
  • MAS1 protein, human
  • Morpholines
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • ets-Domain Protein Elk-1
  • fos-related antigen 1
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • DNA
  • ErbB Receptors
  • PAK1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-raf
  • p21-Activated Kinases