CALRETICULIN MODULATES THE IN-VITRO DNA-BINDING BUT NOT THE IN-VIVO TRANSCRIPTIONAL ACTIVATION BY PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR RETINOID-X RECEPTOR HETERODIMERS

Calreticulin is a ubiquitous calcium binding/storage protein found pri marily in the endoplasmic reticulum. Calreticulin has been shown to in hibit DNA binding and transcriptional activation by glucocorticoid and androgen hormone receptors by binding to the conserved sequence KXFF( K/R)R, present in the DNA-binding domains of all known members of the steroid/nuclear hormone receptor superfamily. To determine whether cal reticulin might be a general regulator of hormone-responsive pathways, we examined its effect on DNA binding in vitro and transcriptional ac tivation in vivo by heterodimers of the peroxisome proliferator-activa ted receptor (PPAR) and the 9-cis retinoic acid receptor (RXR alpha). We show here that purified calreticulin inhibits the binding of PPAR/R XR alpha heterodimers and of other nuclear hormone receptors, to perox isome proliferator-responsive DNA elements in vitro. However, overexpr ession of calreticulin in transiently transfected cultured cells had l ittle or no effect on transactivation mediated by PPAR/RXR alpha. Ther efore, while calreticulin inhibits the binding of both nuclear and ste roid hormone receptors to cognate response elements in vitro, our find ings suggest that calreticulin does not necessarily play an important role in the regulation of all classes of hormone receptors in vivo.