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J. Biol. Chem., Vol. 277, Issue 30, 27517-27527, July 26, 2002

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

Thomas Pusl^§, Julie J. Wu^¶, Tracy L. Zimmerman, Lei Zhang^¶, Barbara E. Ehrlich^¶, Martin W. Berchtold^**, Joannes B. Hoek, Saul J. Karpen, Michael H. Nathanson, and Anton M. Bennett^§§§

From the  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  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.

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