A Phosphatidylinositol 3-kinase-regulated Akt-independent signaling promotes cigarette smoke-induced FRA-1 expression.
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.
Zhang
Qin
Q
Department of Environmental Health Sciences, Bloomberg School of Public Health and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA.
Adiseshaiah
Pavan
P
Kalvakolanu
Dhananjaya V
DV
Reddy
Sekhar P
SP
D002273:Carcinogens / Q000494:pharmacology; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D002867:Chromones / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008954:Models, Biological; D008957:Models, Genetic; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism* / Q000502:physiology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D012907:Smoking; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism*; D054462:p21-Activated Kinases; D000099169:Fos-Related Antigen 1
D002273:Carcinogens; D002867:Chromones; D017362:Cyclic AMP Response Element-Binding Protein; D004247:DNA; D066246:ErbB Receptors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt; D016760:Proto-Oncogene Proteins c-fos; D019908:Proto-Oncogene Proteins c-raf; D012333:RNA, Messenger; D050807:ets-Domain Protein Elk-1; D054462:p21-Activated Kinases; D000099169:Fos-Related Antigen 1; C000715470:MAS1 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C515903:PAK1 protein, human