Depletion of endoplasmic reticulum (ER) Ca2+ store by thapsigargin (Tg) in mammalian cells induces a set of ER protein genes known as the glucose-regulated proteins. Recently, IRE1p, a transmembrane protein postulated to have a serine/threonine kinase activity, has been identified as required for the induction of ER resident proteins genes in Saccharomyces cerevisiae. To investigate whether IRE1p can stimulate mammalian grp transcription, a stable Chinese hamster ovary cell line containing amplified copies of IRE1p has been created. The IRE1p expressing transfectants exhibited a modest (2-fold) enhancement of both the basal and Tg induced level of grp78 and grp94, two coordinately regulated grp genes. Using okadaic acid as a specific inhibitor for the endogenous serine/threonine protein phosphatase activities, a mild (2-fold) stimulative effect was observed for Tg induction of grp78 transcription. The okadaic acid potentiating effect requires a 50-base pair region in the vicinity of the grp78 TATA element. In contrast, the transcriptional activation of grp78 by Tg is almost totally eliminated by genistein, a tyrosine kinase inhibitor. The grp core, the C3 and C1 elements which are major Tg response elements of the rat grp78 promoter, are also major targets of the inhibitive effects of genistein.