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

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 g...

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Published in:	The Journal of biological chemistry Vol. 277; no. 30; pp. 27517 - 27527
Main Authors:	Pusl, Thomas, Wu, Julie J., Zimmerman, Tracy L., Zhang, Lei, Ehrlich, Barbara E., Berchtold, Martin W., Hoek, Joannes B., Karpen, Saul J., Nathanson, Michael H., Bennett, Anton M.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 26-07-2002 American Society for Biochemistry and Molecular Biology
Subjects:	Active Transport, Cell Nucleus Adenosine Triphosphate - metabolism Animals Calcium - metabolism Cell Line Cell Nucleus - metabolism Cytosol - metabolism DNA-Binding Proteins Epidermal Growth Factor - metabolism ets-Domain Protein Elk-1 Gene Expression Regulation Glutathione Transferase - metabolism Humans MAP Kinase Signaling System Microscopy, Fluorescence Models, Genetic Mutagenesis, Site-Directed Parvalbumins - metabolism Phosphorylation Protein Structure, Tertiary Proto-Oncogene Proteins - metabolism Rats Recombinant Fusion Proteins - metabolism Time Factors Transcription Factors Transcription, Genetic Transcriptional Activation
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.M203002200