Reference : Inhibition of nuclear import of calcineurin prevents myocardial hypertrophy.
Scientific journals : Article
Human health sciences : Cardiovascular & respiratory systems
Inhibition of nuclear import of calcineurin prevents myocardial hypertrophy.
Hallhuber, Matthias [> >]
Burkard, Natalie [> >]
Wu, Rongxue [> >]
Buch, Mamta H. [> >]
Engelhardt, Stefan [> >]
Hein, Lutz [> >]
Neyses, Ludwig mailto [University of Luxembourg > Researh Office]
Schuh, Kai [> >]
Ritter, Oliver [> >]
Circulation Research
Yes (verified by ORBilu)
United States
[en] Active Transport, Cell Nucleus/drug effects ; Amino Acid Sequence ; Animals ; Animals, Newborn ; Calcineurin/metabolism ; Cardiomegaly/prevention & control ; Cell Enlargement/drug effects ; Cells, Cultured ; Myocytes, Cardiac/drug effects/pathology ; NFATC Transcription Factors/antagonists & inhibitors/metabolism ; Nuclear Export Signals ; Nuclear Localization Signals/pharmacology ; Peptide Fragments/pharmacology ; Rats ; Rats, Wistar ; beta Karyopherins/metabolism/physiology
[en] The time that transcription factors remain nuclear is a major determinant for transcriptional activity. It has recently been demonstrated that the phosphatase calcineurin is translocated to the nucleus with the transcription factor nuclear factor of activated T cells (NF-AT). This study identifies a nuclear localization sequence (NLS) and a nuclear export signal (NES) in the sequence of calcineurin. Furthermore we identified the nuclear cargo protein importinbeta(1) to be responsible for nuclear translocation of calcineurin. Inhibition of the calcineurin/importin interaction by a competitive peptide (KQECKIKYSERV), which mimicked the calcineurin NLS, prevented nuclear entry of calcineurin. A noninhibitory control peptide did not interfere with the calcineurin/importin binding. Using this approach, we were able to prevent the development of myocardial hypertrophy. In angiotensin II-stimulated cardiomyocytes, [(3)H]-leucine incorporation (159%+/-9 versus 111%+/-11; P<0.01) and cell size were suppressed significantly by the NLS peptide compared with a control peptide. The NLS peptide inhibited calcineurin/NF-AT transcriptional activity (227%+/-11 versus 133%+/-8; P<0.01), whereas calcineurin phosphatase activity was unaffected (298%+/-9 versus 270%+/-11; P=NS). We conclude that calcineurin is not only capable of dephosphorylating NF-AT, thus enabling its nuclear import, but the presence of calcineurin in the nucleus is also important for full NF-AT transcriptional activity.

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