Lead-induced cell signaling cascades in GT1-7 cells.
The effects of lead on the signal transduction pathways that may be involved in the release of gonadotropin-releasing hormone (GnRH) from neurons in the hypothalamus have not been well defined. Using the GT1-7 cell line, an in vitro model for GnRH-secreting neurons, we examined signal transduction pathways directly affected by lead. We found that lead-induced phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1 and ERK2), as well as p90RSK and cAMP response element-binding protein (CREB), but did not induce IkappaB degradation. MEK1/2 inhibitor (PD98059) suppressed lead-induced ERK and p90RSK activation. Neither PKC inhibitors (Go6983, Go6976) nor CaMKII inhibitor (KN-62) had a pronounced effect on lead-induced ERK1 and ERK2 phosphorylation. However, MEK1/2 inhibitor, CaMKII inhibitor, and PKC inhibitor significantly suppressed lead-induced CREB phosphorylation. These results indicate that lead-activated PKC, CaMKII and MEK/ERK/p90RSK pathways simultaneously, all of which contributed to CREB phosphorylation. Our results also indicate that lead-induced p90RSK and CREB activation does not alter expression of early response genes like c-fos. We conclude that lead activates PKC, CaMKII or MEK-ERK-p90RSK pathways in GT1-7 cells, leading to CREB phosphorylation and modulation of gene expression.
Zhang
Quanshun
Q
Department of Biomedical Sciences, Tufts University School of Veterinary Medicine, 200 Westboro Road, N., Grafton, MA 01536, USA.
Bratton
Gerald R
GR
Agarwal
Rajeev K
RK
Calise
David
D
Kugel
Gerard
G
Wan
Yinsheng
Y
Kumar
Amarendra M
AM
D000818:Animals; D015153:Blotting, Western; D002461:Cell Line, Transformed / Q000187:drug effects*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007029:Hypothalamic Neoplasms; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009942:Organometallic Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D044005:Tetrahydroisoquinolines; D013997:Time Factors
D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D009942:Organometallic Compounds; D016760:Proto-Oncogene Proteins c-fos; D044005:Tetrahydroisoquinolines; C058571:soquinolol; D012694:Serine; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C008261:lead acetate