Heat shock-sensitive expression of calreticulin. In vitro and in vivo up-regulation

Calreticulin (CRT) is an ubiquitous, highly conserved, Ca(2+)-binding protein of the sarcoplasmic and endoplasmic reticulum. The precise function(s) of CRT is unknown. However, based on sequence analyses and observations that it may bind to steroid receptors and integrins and store Ca2+ within the cell, it has been postulated to play a "housekeeping" role. To determine whether the level of expression of CRT is affected by stress, we examined the heat shock response of CRT from a variety of cultured cells, including vascular endothelial, lung epithelial, and lung fibroblasts. Following exposure of the cells to 42 degrees C, CRT mRNA transiently accumulated 2.5-4.2-fold at 1-6 h. Nuclear run-on studies and mRNA stability experiments confirmed that the predominant mechanism of augmentation was transcriptional. Chloramphenicol acetyltransferase assays further indicated that the promoter region, containing a putative heat shock element between -172 and -158 of the human CRT gene, is heat shock-sensitive. Finally, we demonstrated the in vivo significance of these findings by exposing rats to hyperthermia. This resulted in accumulation of CRT mRNA and an augmentation of CRT protein in lung tissue. We hypothesize that this stress-induced up-regulation of CRT contributes to the mechanism(s) by which the vascular endothelium and lung tissue, and possibly other organ systems, maintain homeostasis when exposed to a variety of pathophysiological conditions.