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J Biol Chem, Vol. 275, Issue 18, 13872-13878, May 5, 2000
From the Centro de Biología Molecular Severo Ochoa, Consejo
Superior de Investigaciones Científicas-Universidad
Autónoma de Madrid, Facultad de Ciencias, Cantoblanco,
Madrid 28049, Spain
Calcium signals lead to the translocation of
nuclear factor of activated T cells (NFAT) from the cytoplasm to the
nucleus. This process is regulated by the calcium-activated phosphatase calcineurin, which can be cotransported with NFAT to the nucleus to
maintain it transcriptionally active for the duration of calcium signaling. When the calcium signal ceases, NFAT is exported to the
cytoplasm, and different NFAT kinases have been reported to oppose
calcineurin activities and regulate the nuclear export of NFAT. Here we
show that p38 MAPK phosphorylates in vitro and interacts
in vivo with NFATp. Furthermore, the activation of this pathway in HeLa cells by cotransfection with activated MKK6 and p38
counteracts the calcium-induced nuclear accumulation of NFATp but not
that of NFATc. By contrast, activation of JNK or ERK pathways failed to
modify the nuclear shuttling of NFATp. Consistently, activation of p38,
but not the JNK MAPK pathway, results in the inhibition of NFATp-driven
transcription. In addition, the inhibition of the nuclear accumulation
of NFATp by p38 appears to be mediated through the activation of NFATp
nuclear export and takes place in a Leptomycin B-sensitive fashion,
suggesting the involvement of the exportin CRM1 in this process. Thus,
the p38 signal transduction pathway appears to play an important role
in the regulation of the nuclear shuttling of NFATp and in cellular homeostasis.
A Role for the p38 MAP Kinase Pathway in the Nuclear
Shuttling of NFATp*
,
*
This work was supported by Grant PM96-0076 from Ministerio
de Educación y Cultura of Spain and Grants 8.3/011/97 and
8.3/19/1998 from the Comunidad Autónoma de Madrid (to J. M. R.). The Centro de Biología Molecular Severo Ochoa is
supported by a grant from the Fundación Ramón Areces.The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by a Formación del Personal Investigador
Fellowship from the Comunidad Autónoma de Madrid.
§
Supported by a Formación del Personal Investigador Fellowship
from the Ministerio de Educación y Cultura of Spain.
¶
Recipient of a Fulbright Fellowship.
To whom correspondence should be addressed. Tel.:
34-91-397-8270; Fax: 34-91-397-8087; E-mail:
jmredondo@cbm.uam.es.
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