The calcium-regulated protein phosphatase calcineurin (PP2B) functions as a 
regulator of gene expression in diverse tissues through the dephosphorylation 
and activation of a family of transcription factors known as nuclear factor of 
activated T cells (NFAT). Here we show that NFATc3, in addition to being calcium 
responsive, is regulated through an indirect recruitment of class II histone 
deacetylases (HDACs). Specifically, yeast two-hybrid screening with the rel 
homology domain of NFATc3 identified the chaperone mammalian relative of DnaJ 
(Mrj) as a specific interacting factor. Mrj and NFATc3 were shown to directly 
associate with one another in mammalian cells and in vitro. Mrj served as a 
potent inhibitor of NFAT transcriptional activity within the nucleus through a 
mechanism involving histone deacetylase recruitment in conjunction with heat 
shock stimulation. Indeed, Mrj was determined to interact with class II histone 
deacetylases, each of which translocated to the nucleus following heat shock 
stimulation. Mrj also decreased NFATc3 occupancy of the tumor necrosis 
factor-alpha promoter in cardiomyocytes in an HDAC-dependent manner, and Mrj 
blocked calcineurin-induced cardiomyocyte hypertrophic growth. Conversely, 
small-interfering-RNA-mediated reduction of Mrj augmented NFAT transcriptional 
activity and spontaneously induced cardiac myocyte growth. Collectively, our 
results define a novel response pathway whereby NFATc3 is negatively regulated 
by class II histone deacetylases through the DnaJ (heat shock protein-40) 
superfamily member Mrj.