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© The Rockefeller University Press, 0021-9525/2003/5/497 $5.00
The Journal of Cell Biology, Volume 161, Number 3, 497-505

Oscillatory nucleocytoplasmic shuttling of the general stress response transcriptional activators Msn2 and Msn4 in Saccharomyces cerevisiae

¹ Laboratoire Information Génétique et Développement, Institut de Génétique et Microbiologie, Centre National de la Recherche Scientifique (CNRS)/UPS UMR 8621, Université Paris-Sud, F-914905 Orsay cedex, France
² Institut Curie, CNRS-UMR 146, F-91405 Orsay cedex, France
³ Unité de Chronobiologie théorique, Faculté des Sciences, Université Libre de Bruxelles, B-1050 Brussels, Belgium

Address correspondence to Michel Jacquet, Institut de Génétique et Microbiologie, UMR 8621 CNRS Université, Bat 400, Université Paris-Sud, 91405 Orsay cedex, France. Tel.: 33-169-15-7963. Fax: 33-169-15-4629. E-mail: michel.jacquet{at}igmors.u-psud.fr

Msn2 and Msn4 are two related transcriptional activators that mediate a general response to stress in yeast Saccharomyces cerevisiae by eliciting the expression of specific sets of genes. In response to stress or nutritional limitation, Msn2 and Msn4 migrate from the cytoplasm to the nucleus. Using GFP-tagged constructs and high-resolution time-lapse video microscopy on single cells, we show that light emitted by the microscope also triggers this migration. Unexpectedly, the population of Msn2 or Msn4 molecules shuttles repetitively into and out of the nucleus with a periodicity of a few minutes. A large heterogeneity in the oscillatory response to stress is observed between individual cells. This periodic behavior, which can be induced by various types of stress, at intermediate stress levels, is not dependent upon protein synthesis and persists when the DNA-binding domain of Msn2 is removed. The cAMP–PKA pathway controls the sensitivity of the oscillatory nucleocytoplasmic shuttling. In the absence of PKA, Msn4 continues to oscillate while Msn2 is maintained in the nucleus. We show that a computational model based on the possibility that Msn2 and Msn4 participate in autoregulatory loops controlling their subcellular localization can account for the oscillatory behavior of the two transcription factors.

Key Words: stress response; signaling; nuclear localization; imaging; computational model

J. De Mey's present address is École Supérieure de Biotechnologie de Strasbourg, CNRS-UMR 7100, 1, Bld. Sébastien Brant, F-67400 Illkirch-Graffenstaden, France.

^* Abbreviation used in this paper: STRE, stress response element.

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