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J. Cell Biol.,
Volume 142, Number 3, August 10, 1998 625-633
Centre de Biochimie-Centre National de la Recherche Scientifique (CNRS) UMR 6543, Université de Nice, 06108 Nice, France
Mitogen-activated protein kinases (p42/p44
MAPK, also called Erk2 and Erk1) are key mediators
of signal transduction from the cell surface to the nucleus. We have previously shown that the activation of
p42/p44 MAPK required for transduction of mitogenic signaling is associated with a rapid nuclear translocation of these kinases. However, the means by which p42
and p44 MAPK translocate into the nucleus after cytoplasmic activation is still not understood and cannot
simply be deduced from their protein sequences. In this
study, we have demonstrated that activation of the p42/
p44 MAPK pathway was necessary and sufficient for
triggering nuclear translocation of p42 and p44 MAPK.
First, addition of the MEK inhibitor PD 98059, which
blocks activation of the p42/p44 MAPK pathway, impedes the nuclear accumulation, whereas direct activation of the p42/p44 MAPK pathway by the chimera
Raf-1:ER is sufficient to promote nuclear accumulation of p42/p44 MAPK. In addition, we have shown
that this nuclear accumulation of p42/p44 MAPK required the neosynthesis of short-lived proteins. Indeed,
inhibitors of protein synthesis abrogate nuclear accumulation in response to serum and accelerate p42/p44
MAPK nuclear efflux under conditions of persistent
p42/p44 MAPK activation. In contrast, inhibition of
targeted proteolysis by the proteasome synergistically
potentiated p42/p44 MAPK nuclear localization by
nonmitogenic agonists and markedly prolonged nuclear
localization of p42/p44 MAPK after mitogenic stimulation. We therefore conclude that the MAPK nuclear translocation requires both activation of the p42/p44
MAPK module and neosynthesis of short-lived proteins that we postulate to be nuclear anchors.
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