Mechanisms of Signal Transduction
Identification of the MLL2 Complex as a Coactivator for Estrogen Receptor α*

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A novel estrogen receptor (ER)α coactivator complex, the MLL2 complex, which consists of MLL2, ASH2, RBQ3, and WDR5, was identified. ERα directly binds to the MLL2 complex through two LXXLL motifs in a region of MLL2 near the C terminus in a ligand-dependent manner. Disrupting the interaction between ERα and the MLL2 complex with small interfering RNAs specific against MLL2 or an MLL2 fragment representing the interacting region with ERα significantly inhibited the ERα transcription activity. The MLL2 complex was recruited on promoters of ERα target genes along with ERα upon estrogen stimulation. Inhibition of MLL2 expression decreased the estrogen-induced expression of ERα target genes cathepsin D and to a lesser extent pS2. In addition, MCF-7 cell growth was also inhibited by the depletion of MLL2. These results demonstrate that the ERα signaling pathway is critically dependent on its direct interaction with the MLL2 complex and suggest a central role for the MLL2 complex in the growth of ERα-positive cancer cells.

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This work was supported by National Institutes of Health Grants K08 ES 00356 and CA 88898 (to Y. J. Z.) and CA 84472 (to M. S. R.) and Department of Defense Breast Cancer Research Program (to Y. J. Z.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental material.