The perturbation of the endoplasmic reticulum (ER) homeostasis by the pharmacological agents or mutant secretory proteins invokes the adaptive cellular reaction, unfolded protein response (UPR). Here we show the activation of UPR under the physiological conditions of the hormone-stimulated expression of thyroglobulin (Tg), the major secretory product of thyroid cells. The early increase in the Tg synthesis within 1 h after stimulation apparently triggers UPR as it is evidenced by the activation of ATF6- and PERK-dependent pathways of UPR and subsequent expression of the UPR target genes, ER molecular chaperones. However, little or no activation of the other UPR sensor, IRE1, was observed, as judged by the absence of the spliced mRNA of its downstream effector, transcription factor XBP1. We conclude that the physiological UPR in differentiating thyrocytes differs substantially from the drug-induced stress by its weaker manifestation and distinct pattern of the activation of UPR sensors. (C) 2004 Elsevier Inc. All rights reserved.