MODULATION OF GENE-EXPRESSION BY CALRETICULIN BINDING TO THE GLUCOCORTICOID RECEPTOR

CALRETICULIN is a multifunctional protein that acts as a major Ca2+-bi nding (storage) protein in the lumen of the endoplasmic reticulum1. It is also found in the nucleus2, suggesting that it may have a role in transcription regulation. Calreticulin has been reported to bind to th e synthetic peptide KLGFFKR3, which is almost identical to an amino-ac id sequence in the DNA-binding domain of the superfamily of nuclear re ceptors4-6. Could calreticulin interact with the DNA-binding domain of these receptors and affect their function? Here we report that the am ino terminus of calreticulin interacts with the DNA-binding domain of the glucocorticoid receptor and prevents the receptor from binding to its specific glucocorticoid response element. Overexpression of calret iculin in mouse L fibroblasts inhibits glucocorticoid-response-mediate d transcriptional activation of a glucocorticoid-sensitive reporter ge ne and of the endogenous, glucocorticoid-sensitive gene encoding cytoc hrome P450. Together these results indicate that calreticulin may be i mportant in gene transcription, regulating the glucocorticoid receptor and perhaps other members of the superfamily of nuclear receptors.