Transcription Requires a Nuclear Signal

Abstract

Stimuli that increase intracellular cytosolic calcium concentrations sometimes also stimulate an increase in nuclear calcium concentration. Pusl et al. targeted the calcium-binding protein parvalbumin to the cytosol (with a nuclear export signal) or to the nucleus (with a nuclear localization signal) to selectively inhibit cytosolic or nuclear increases in calcium concentration. They used a chimera between the Gal4 DNA binding domain and the mitogen-activated protein kinase (MAPK) target Elk-1 to stimulate reporter gene expression in the presence of the calcium-buffering parvalbumin. Expression of the nuclear-localized parvalbumin selectively inhibited expression from the reporter gene stimulated by the addition of epidermal growth factor (EGF) to activate the MAPK pathway, whereas parvalbumin in the cytosol did not. Nuclear-localized parvalbumin did not inhibit phosphorylation or nuclear localization of the MAPK extracellular-signal-related kinase 2 (ERK2), nor did it inhibit the phosphorylation or translocation of Elk-1. Treatment of the cells with ionomycin to artificially increase calcium concentrations stimulated Elk-1 phosphorylation and translocation but did not stimulate transcription. Thus, calcium alone cannot substitute for a physiological stimulus supplied by EGF. The authors propose that growth factors stimulate multiple signals that result in transcriptional activation, one of which is an increase in nuclear calcium concentration. T. Pusl, J. J. Wu, T. L. Zimmerman, L. Zhang, B. E. Ehrlizh, M. W. Berchtold, J. B. Hoek, S. J. Karpen, M. H. Nathanson, A. M. Bennett, Epidermal growth factor-mediated activation of the ETS domain transcription factor Elk-1 requires nuclear calcium. J. Biol. Chem. 277 , 27517-27527 (2002). [Abstract] [Full Text]