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Potent Ligand-Independent Estrogen Receptor Activation by 3,3'-Diindolylmethane Is Mediated by Cross Talk between the Protein Kinase A and Mitogen-Activated Protein Kinase Signaling Pathways

Departments of Nutritional Sciences and Toxicology (H.L., J.E.R., L.F.B.) and Molecular and Cell Biology (G.L.F.), University of California, Berkeley, California 94720

Address all correspondence and requests for reprints to: Leonard F. Bjeldanes, Department of Nutritional Sciences and Toxicology, 115 Morgan Hall, University of California-Berkeley, Berkeley, California 94720. E-mail: lfb{at}nature berkeley.edu.

We investigated the mechanism of ligand-independent activation of the estrogen receptor (ER) by 3,3'-diindolylmethane (DIM), a promising anticancer agent derived from vegetables of the Brassica genus, in Ishikawa and HEC-1B human endometrial cancer cells. DIM stimulated the activity of an ER-responsive reporter by over 40-fold, equivalent to the maximum induction produced by estradiol (E2), whereas cotreatment of cells with the ER antagonist, ICI-182,780 (ICI), abolished the stimulatory effect of DIM. DIM also induced the expressions of the endogenous genes, TGF-, alkaline phosphatase, and progesterone receptor similar to levels induced by E2. Induction of gene expression by DIM was inhibited by the protein synthesis inhibitor, cycloheximide. In addition, cotreatment of cells with the protein kinase A (PKA) inhibitor, H89, or the MAPK inhibitor, PD98059, reduced DIM activation of the ER by 75% and 50%, respectively. Simultaneous treatment of cells with both inhibitors completely abolished the effect of DIM. DIM stimulated MAPK activity and induced phosphorylation of the endogenous PKA target, cAMP response element binding protein (CREB), in a PKA-dependent manner. Expression of MCREB, a nonphosphorylatable CREB mutant, partially abolished activation of the ER by DIM. These results demonstrate that DIM is a mechanistically novel activator of the ER that requires PKA-dependent phosphorylation of CREB.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Ligands:   17β-Estradiol

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