Opposite effects of inhibitors of mitogen-activated protein kinase pathways on the egr-1 and beta-globin expression in erythropoietin-responsive murine erythroleukemia cells.
The effect of erythropoietin (Epo) on the expression of mitogen-activated protein kinase (MAPK) target genes egr-1 and c-fos was investigated in Epo-responsive murine erythroblastic cell line ELM-I-1. Epo induced a transient rise in egr-1 mRNA without a similar effect on c-fos expression. The induction of egr-1 correlated with a rapid ERK1/2 phosphorylation and was prevented with MEK1/2 inhibitors PD 98059 and UO126. The p38 inhibitor SB 203580 enhanced ERK1/2 phosphorylation and egr-1 mRNA levels. Longer incubations of ELM-I-1 cells with Epo revealed a second later phase of increase in egr-1 expression which was also prevented by MEK1/2 inhibitors, whereas SB 203580 had a stimulatory effect. In contrast, the beta-globin mRNA production was enhanced in the presence of PD 98059 and UO126 and reduced by SB 203580. The results suggest a regulatory role of egr-1 expression in Epo signal transduction and provide pharmacological evidence for the negative modulation of differentiation-specific gene expression by the ERK1/2 pathway in murine erythroleukemia cells.
Schaefer
András
A
Institute of Toxicology, Hamburg University Medical School and Department of Environmental Medicine and Toxicology, Umweltmedizin Hamburg e.V., Vogt-Kölln-Strasse 30, 22527 Hamburg, Germany. aschaefe@uke.uni-hamburg.de
Kósa
Ferenc
F
Bittorf
Thomas
T
Magócsi
Mária
M
Rosche
Anette
A
Ramirez-Chávez
Yoandra
Y
Marotzki
Stefan
S
Marquardt
Hans
H
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004921:Erythropoietin / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005914:Globins / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000378:metabolism*; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D002070:Butadienes; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D017874:Immediate-Early Proteins; D009570:Nitriles; D016760:Proto-Oncogene Proteins c-fos; D011725:Pyridines; D014157:Transcription Factors; C113580:U 0126; D004921:Erythropoietin; D005914:Globins; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one