The proto-oneoprotein Brx activates estrogen receptor β 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 ER alpha via a Cdc42-dependent pathway. Brx also significantly enhances ligand-dependent activity of ER beta. 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 ER beta activity by Brx, showing that p38 MAPK activity is required for the enhancement of ER beta 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 ER beta. Our findings suggest that p38 MAPKs may be important regulators of ER beta activity.