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J. Biol. Chem., Vol. 279, Issue 37, 38294-38302, September 10, 2004

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Melatonin, an Endogenous-specific Inhibitor of Estrogen Receptor via Calmodulin^*

Beatriz del Río, Juana M. García Pedrero¶, Carlos Martínez-Campa¶, Pedro Zuazua||, Pedro S. Lazo, and Sofía Ramos**

From the Departamento de Bioquímica y Biología Molecular and Instituto Universitario de Oncología Del Principado de Asturias, Universidad de Oviedo, 33071 Oviedo, Spain

Melatonin is an indole hormone produced mainly by the pineal gland. We have previously demonstrated that melatonin interferes with estrogen (E₂) signaling in MCF7 cells by impairing estrogen receptor (ER) pathways. Here we present the characterization of its mechanism of action showing that melatonin is a specific inhibitor of E₂-induced ER-mediated transcription in both estrogen response element- and AP1-containing promoters, whereas ER-mediated transactivation is not inhibited or even activated at certain promoters. We show that the sensitivity of MCF-7 cells to melatonin depends on the ER/ER ratio, and ectopic expression of ER results in MCF-7 cells becoming insensitive to this hormone. Melatonin acts as a calmodulin antagonist inducing conformational changes in the ER-calmodulin (CaM) complex, thus impairing the binding of E₂·ER·CaM complex to DNA and, therefore, preventing ER-dependent transcription. Moreover the mutant ER (K302G,K303G), unable to bind calmodulin, becomes insensitive to melatonin. The effect of melatonin is specific since other related indoles neither interact with CaM nor inhibit ER-mediated transactivation. Interestingly, melatonin does not affect the binding of coactivators to ER, indicating that melatonin action is different from that of current therapeutic anti-estrogens used in breast cancer therapy. Thus, they target ER at different levels, representing two independent ways to control ER activity. It is, therefore, conceivably a synergistic pharmacological effect of melatonin and current anti-estrogen drugs.

Received for publication, March 22, 2004 , and in revised form, June 21, 2004.

^* This work was supported by Comisión Interministerial de Ciencia y Tecnología, Spain (CICYT) Grant SAF/96-0132, Fondo de Investigaciones Sanitarias Grant 00/1086, and CICYT Grant SAF/98-0174.

These authors equally contributed to this work.

Recipient of a fellowship from Fundación Científica de la Asociación Española Contra el Cáncer.

^¶ Recipients of a fellowship from Instituto Universitario de Oncología del Principado de Asturias, Obra Social Cajastur.

^|| Recipient of a fellowship from Fondo de Investigaciones Sanitarias.

^** To whom correspondence should be addressed. Tel.: 34-985-10-35-69; Fax: 34-985-10-31-57; E-mail: sramos{at}uniovi.es.

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