ERp72, a resident protein of the endoplasmic reticulum (ER) is both a stress protein and a member of the protein disulfide isomerase family of proteins. Analysis of the murine ERp72 promoter region revealed the presence of potential transcriptional control elements characteristic of the promoters of mammalian ER proteins. These include multiple CCAAT elements and Sp1 and AP-2 consensus sequences. Functional analysis of mutations in the ERp72 promoter and 5'-flanking region revealed an 82-bp fragment that is sufficient to mediate the stimulation observed for ERp72 either by stress or by the expression of incompletely assembled immunoglobulin mu heavy chain in the ER. This 82-bp fragment contains two CCAAT elements but little additional homology to protein traffic-responsive sequences of other members of the ER stress family. This suggests that the ERp72 gene contains a novel element that is the target of an intracellular signaling pathway initiated by protein traffic in the ER.