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Submitted on May 27, 2003
Accepted on November 18, 2003
1 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, CA 94720
* To whom correspondence should be addressed. 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) while 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, transforming growth factor-
(TGF-), alkaline phosphatase (AP), and progesterone receptor (PR) 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 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, cyclic AMP 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.
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