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Constitutively elevated nuclear export activity opposes Ca2+-dependent NFATc3 nuclear accumulation in vascular smooth muscle: role of JNK2 and Crm-1

Gomez, Maria LU ; Bosc, Laura V Gonzalez; Stevenson, Andra S; Wilkerson, M Keith; Hill-Eubanks, David C and Nelson, Mark T (2003) In Journal of Biological Chemistry 278(47). p.46847-46853
Abstract
The transcription factor NFAT (nuclear factor of activated T-cells) is a cytosolic phosphoprotein that accumulates in the nucleus following dephosphorylation by the calcium (Ca2+)/calmodulin-dependent phosphatase, calcineurin. A defining feature of stimuli that induce NFAT nuclear accumulation/activation is a sustained increase in global intracellular Ca2+. Contrary to expectations, we have found that a sustained elevation of intracellular Ca2+, induced by membrane potential depolarization and mediated by voltage-dependent Ca2+ channels, does not result in nuclear localization of the NFATc3 isoform in smooth muscle. However, vasoconstrictors (e.g. uridine triphosphate (UTP)) and growth factors, which elevate intracellular Ca2+ and engage... (More)
The transcription factor NFAT (nuclear factor of activated T-cells) is a cytosolic phosphoprotein that accumulates in the nucleus following dephosphorylation by the calcium (Ca2+)/calmodulin-dependent phosphatase, calcineurin. A defining feature of stimuli that induce NFAT nuclear accumulation/activation is a sustained increase in global intracellular Ca2+. Contrary to expectations, we have found that a sustained elevation of intracellular Ca2+, induced by membrane potential depolarization and mediated by voltage-dependent Ca2+ channels, does not result in nuclear localization of the NFATc3 isoform in smooth muscle. However, vasoconstrictors (e.g. uridine triphosphate (UTP)) and growth factors, which elevate intracellular Ca2+ and engage multiple intracellular signaling pathways, induce a robust increase in smooth muscle nuclear NFATc3. Here we show that depolarizing stimuli that normally fail to induce NFATc3 nuclear accumulation in arterial smooth muscle effectively induce nuclear accumulation under conditions in which Crm-1-dependent or JNK2-mediated nuclear export processes are disrupted. Consistent with an important regulatory role for JNK, UTP exerts a suppressive effect on JNK activity in smooth muscle. Export of nuclear NFATc3 following UTP-induced nuclear accumulation is dramatically slowed in cerebral arteries from JNK2-/- animals. These data indicate that in smooth muscle, stimulation of Ca2+-dependent, calcineurin-mediated nuclear import and suppression of Crm-1/JNK-dependent nuclear export are both required for induction of NFATc3 nuclear accumulation. These results highlight the dynamic interplay between influences that promote and oppose NFAT nuclear accumulation and suggest that in arterial smooth muscle suppression of constitutive nuclear export activity is an important property of NFAT-activating stimuli. (Less)
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author
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
278
issue
47
pages
46847 - 46853
publisher
ASBMB
external identifiers
  • pmid:12954637
  • scopus:0345306626
ISSN
1083-351X
DOI
language
English
LU publication?
no
id
d485301f-3290-4b32-af13-6ad3cf7673ce (old id 1126533)
date added to LUP
2008-06-11 11:12:00
date last changed
2018-05-29 12:04:54
@article{d485301f-3290-4b32-af13-6ad3cf7673ce,
  abstract     = {The transcription factor NFAT (nuclear factor of activated T-cells) is a cytosolic phosphoprotein that accumulates in the nucleus following dephosphorylation by the calcium (Ca2+)/calmodulin-dependent phosphatase, calcineurin. A defining feature of stimuli that induce NFAT nuclear accumulation/activation is a sustained increase in global intracellular Ca2+. Contrary to expectations, we have found that a sustained elevation of intracellular Ca2+, induced by membrane potential depolarization and mediated by voltage-dependent Ca2+ channels, does not result in nuclear localization of the NFATc3 isoform in smooth muscle. However, vasoconstrictors (e.g. uridine triphosphate (UTP)) and growth factors, which elevate intracellular Ca2+ and engage multiple intracellular signaling pathways, induce a robust increase in smooth muscle nuclear NFATc3. Here we show that depolarizing stimuli that normally fail to induce NFATc3 nuclear accumulation in arterial smooth muscle effectively induce nuclear accumulation under conditions in which Crm-1-dependent or JNK2-mediated nuclear export processes are disrupted. Consistent with an important regulatory role for JNK, UTP exerts a suppressive effect on JNK activity in smooth muscle. Export of nuclear NFATc3 following UTP-induced nuclear accumulation is dramatically slowed in cerebral arteries from JNK2-/- animals. These data indicate that in smooth muscle, stimulation of Ca2+-dependent, calcineurin-mediated nuclear import and suppression of Crm-1/JNK-dependent nuclear export are both required for induction of NFATc3 nuclear accumulation. These results highlight the dynamic interplay between influences that promote and oppose NFAT nuclear accumulation and suggest that in arterial smooth muscle suppression of constitutive nuclear export activity is an important property of NFAT-activating stimuli.},
  author       = {Gomez, Maria and Bosc, Laura V Gonzalez and Stevenson, Andra S and Wilkerson, M Keith and Hill-Eubanks, David C and Nelson, Mark T},
  issn         = {1083-351X},
  language     = {eng},
  number       = {47},
  pages        = {46847--46853},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Constitutively elevated nuclear export activity opposes Ca2+-dependent NFATc3 nuclear accumulation in vascular smooth muscle: role of JNK2 and Crm-1},
  url          = {http://dx.doi.org/},
  volume       = {278},
  year         = {2003},
}