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J. Biol. Chem. 277 (30): 27517-27527

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Epidermal Growth Factor-mediated Activation of the ETS Domain Transcription Factor Elk-1 Requires Nuclear Calcium*

Thomas PuslDagger §, Julie J. Wu, Tracy L. Zimmerman||, Lei Zhang, Barbara E. Ehrlich, Martin W. Berchtold**, Joannes B. HoekDagger Dagger , Saul J. Karpen||, Michael H. NathansonDagger , and Anton M. Bennett§§§

From the Dagger  Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, the  Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, the || Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, the ** Department of Molecular Cell Biology, University of Copenhagen, 1353 Copenhagen, Denmark, and the Dagger Dagger  Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Cytosolic and nuclear Ca2+ have been shown to differentially regulate transcription. However, the impact of spatially distinct Ca2+ signals on mitogen-activated protein kinase-mediated gene expression remains unknown. Here we investigated the role of nuclear and cytosolic Ca2+ signals in epidermal growth factor (EGF)-induced transactivation of the ternary complex factor Elk-1 using a GAL4-Elk-1 construct. EGF increased Ca2+ in both the nucleus and cytosol of HepG2 or 293 cells. Pretreatment with the intracellular Ca2+ chelator bis(2-aminophenyl)ethyleneglycol-N,N,N',N'-tetraacetic acid significantly reduced EGF-induced transactivation of Elk-1, indicating that EGF-stimulated Elk-1 transcriptional activity is dependent on intracellular Ca2+. To determine the relative contribution of nuclear and cytosolic Ca2+ signals during EGF-mediated Elk-1 transactivation, Ca2+ signals in either compartment were selectively impaired by targeted expression of the Ca2+-binding protein parvalbumin to either the nucleus or cytosol. Suppression of nuclear but not cytosolic Ca2+ signals inhibited EGF-induced transactivation of Elk-1. However, suppression of nuclear Ca2+ signals did not affect the ability of ERK either to become phosphorylated or to undergo translocation to the nucleus in response to EGF. Elk-1 phosphorylation and nuclear localization following EGF stimulation were also unaffected by suppressing nuclear Ca2+ signals. These results suggest that nuclear Ca2+ is required for EGF-mediated transcriptional activation of Elk-1 and that phosphorylation of Elk-1 alone is not sufficient to induce its transcriptional activation in response to EGF. Thus, subcellular targeting of parvalbumin reveals a distinct role for nuclear Ca2+ signals in mitogen-activated protein kinase-mediated gene transcription.

* This work was supported by grants from the National Institutes of Health and the American Heart Association.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported by a grant from the American Liver Foundation and Deutsche Forschungsgemeinschaft.

§§ To whom correspondence should be addressed: Yale University School of Medicine, Dept. of Pharmacology, SHM B230, 333 Cedar St., New Haven, CT 06520-8066. Tel.: 203-737-2441; Fax: 203-785-4395; E-mail: anton.bennett@yale.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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