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Calmodulin Is a Selective Modulator of Estrogen Receptors

Departamento de Bioquímica y Biología Molecular and Instituto Universitario de Oncología Principado de Asturias (J.M.G.P., B.R., C.M.-C., P.S.L., S.R.), Universidad de Oviedo, 33007 Oviedo, Spain; and Department of Biochemistry (M.M.), Saitama Medical School, Moromaya-Machi Iruma Gum, Saitama 350-04, Japan

Address all correspondence and requests for reprints to: S. Ramos, Departamento de Bioquímica y Biología Molecular. Instituto Universitario de Oncología Principado de Asturias. Universidad de Oviedo, 33007 Oviedo, Spain. E-mail: srg{at}sauron.quimica.uniovi.es.

In the search for differences between ER and ERß, we analyzed the interaction of both receptors with calmodulin (CaM) and demonstrated that ER but not ERß directly interacts with CaM. Using transiently transfected HeLa cells, we examined the effect of the CaM antagonist N-(6-aminohexyl)-5-chloro-naphthalene sulfonilamide hydrochloride (W7) on the transactivation properties of ER and ERß in promoters containing either estrogen response elements or activator protein 1 elements. Transactivation by ER was dose-dependently inhibited by W7, whereas that of ERß was not inhibited or even activated at low W7 concentrations. In agreement with these results, transactivation of an estrogen response element containing promoter in MCF-7 cells (which express a high ER/ERß ratio) was also inhibited by W7. In contrast, transactivation in T47D cells (which express a low ER/ERß ratio) was not affected by this CaM antagonist. The sensitivity of MCF-7 cells to W7 was abolished when cells were transfected with increasing amounts of ERß, indicating that the sensitivity to CaM antagonists of estrogen-responsive tissues correlates with a high ER/ERß ratio. Finally, substitution of lysine residues 302 and 303 of ER for glycine rendered a mutant ER unable to interact with CaM whose transactivation activity became insensitive to W7. Our results indicate that CaM antagonists are selective modulators of ER able to inhibit ER-mediated activity, whereas ERß actions were not affected or even potentiated by W7.

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