The proto-oncoprotein Brx activates estrogen receptor beta by a p38 mitogen-activated protein kinase pathway.
The estrogen receptors (ERs) are ligand-inducible transcription factors that play key roles in the control of growth and differentiation in reproductive tissues. We showed that the novel Dbl family proto-oncoprotein Brx enhances ligand-dependent activity of ERalpha via a Cdc42-dependent pathway. Brx also significantly enhances ligand-dependent activity of ERbeta. This enhancement is not affected by inhibition of p44/42 mitogen-activated protein kinase (MAPK) activation by PD98059. However, addition of the p38 MAPK inhibitor SB202190 abrogates the enhancement of ERbeta activity by Brx, showing that p38 MAPK activity is required for the enhancement of ERbeta function by Brx. In COS-7 cells, transfection of Brx leads to activation of endogenous p38 MAPK activity. Co-expression of the beta2 isoform of human p38 MAPK and a constitutively active form of the p38 MAPK kinase MKK6 (MKK6-EE) synergistically augments ligand-dependent activity of ERbeta. Our findings suggest that p38 MAPKs may be important regulators of ERbeta activity.
Driggers
P H
PH
Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. pdriggers@rocketmail.com
Segars
J H
JH
Rubino
D M
DM
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047629:Estrogen Receptor beta; D005419:Flavonoids / Q000494:pharmacology; D017930:Genes, Reporter; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D008024:Ligands; D048669:MAP Kinase Kinase 6; D020935:MAP Kinase Signaling System; D015778:Minor Histocompatibility Antigens; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D015513:Oncogene Proteins / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D014018:Tissue Distribution; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D054758:A Kinase Anchor Proteins; C085467:AKAP13 protein, human; D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; D047629:Estrogen Receptor beta; D005419:Flavonoids; D007093:Imidazoles; D008024:Ligands; D015778:Minor Histocompatibility Antigens; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one