Inhibition of nuclear import of calcineurin prevents myocardial hypertrophy.
Circ Res
; 99(6): 626-35, 2006 Sep 15.
Article
em En
| MEDLINE
| ID: mdl-16931796
ABSTRACT
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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Bases de dados:
MEDLINE
Assunto principal:
Cardiomegalia
/
Calcineurina
/
Sinais de Localização Nuclear
/
Transporte Ativo do Núcleo Celular
/
Miócitos Cardíacos
/
Fatores de Transcrição NFATC
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Circ Res
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Alemanha