Published online before print August 24, 2006, doi: 10.1161/01.RES.0000243208.59795.d8
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Submitted on March 10, 2006
Revised on August 11, 2006
Accepted on August 16, 2006
Inhibition of Nuclear Import of Calcineurin Prevents Myocardial Hypertrophy
Matthias Hallhuber ;
From the Department of Medicine I (M.H., N.B., R.W., O.R.); Institute of Physiology (K.S.); and Rudolf-Virchow-Center (S.E.), DFG-Research Center for Experimental Biomedicine, University of Wuerzburg, Germany; University Department of Medicine (M.H.B., L.N.), Manchester Royal Infirmary, UK; and Department II (L.H.), Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Germany.
* To whom correspondence should be addressed. E-mail: Ritter_O{at}klinik.uni-wuerzburg.de.
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 importin
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, [3H]-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.
Key words: angiotensin II • calcineurin • gene regulation • hypertrophy • NF-AT • nuclear-localizing signals
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