HEAT SHOCK-SENSITIVE EXPRESSION OF CALRETICULIN - IN-VITRO AND IN-VIVO UP-REGULATION

Calreticulin (CRT) is an ubiquitous, highly conserved, Ca2+-binding pr otein of the sarcoplasmic and endoplasmic reticulum. The precise funct ion(s) of CRT is unknown. However, based on sequence analyses and obse rvations 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 affect ed by stress, we examined the heat shock response of CRT from a variet y 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-o n studies and mRNA stability experiments confirmed that the predominan t mechanism of augmentation was transcriptional. Chloramphenieol acety ltransferase assays further indicated that the promoter region, contai ning a putative heat shock element between -172 and -158 of the human CRT gene, is heat shock-sensitive. Finally, we demonstrated the in viv o significance of these findings by exposing rats to hyperthermia. Thi s resulted in accumulation of CRT mRNA and an augmentation of CRT prot ein in lung tissue. We hypothesize that this stress-induced up-regulat ion of CRT contributes to the mechanism(s) by which the vascular endot helium and lung tissue, and possibly other organ systems, maintain hom eostasis when exposed to a variety of pathophysiological conditions.