Modulation of gene expression by calreticulin binding to the glucocorticoid receptor.
Calreticulin is a multifunctional protein that acts as a major Ca(2+)-binding (storage) protein in the lumen of the endoplasmic reticulum. It is also found in the nucleus, suggesting that it may have a role in transcription regulation. Calreticulin has been reported to bind to the synthetic peptide KLGFFKR, which is almost identical to an amino-acid sequence in the DNA-binding domain of the superfamily of nuclear receptors. Could calreticulin interact with the DNA-binding domain of these receptors and affect their function? Here we report that the amino 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 calreticulin in mouse L fibroblasts inhibits glucocorticoid-response-mediated transcriptional activation of a glucocorticoid-sensitive reporter gene and of the endogenous, glucocorticoid-sensitive gene encoding cytochrome P450. Together these results indicate that calreticulin may be important in gene transcription, regulating the glucocorticoid receptor and perhaps other members of the super-family of nuclear receptors.
Burns
K
K
Cardiovascular Disease Research Group, University of Alberta, Edmonton, Canada.
Duggan
B
B
Atkinson
E A
EA
Famulski
K S
KS
Nemer
M
M
Bleackley
R C
RC
Michalak
M
M
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002135:Calcium-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D037282:Calreticulin; D002467:Cell Nucleus / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004247:DNA / Q000378:metabolism; D017931:DNA Primers; D004926:Escherichia coli; D005786:Gene Expression Regulation / Q000502:physiology*; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007739:L Cells; D051379:Mice; D008969:Molecular Sequence Data; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism* / Q000502:physiology
D002135:Calcium-Binding Proteins; D037282:Calreticulin; D017931:DNA Primers; D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; D012261:Ribonucleoproteins; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase