Endoplasmic reticulum (ER) stress is involved in a wide range of pathologies. Detection and monitoring of the unfolded protein response are required to disclose the link between ER stress and diseases. Assessment of ER stress is also essential for evaluation of therapeutic drugs in vitro and in vivo; that is, their therapeutic utility as well as adverse effects. For detection and monitoring of ER stress in living cells and animals, ER stress-responsive alkaline phosphatase (ESTRAP), also called secreted alkaline phosphatase (SEAP), serves as a useful indicator. In cells genetically engineered to express SEAP, secretion of SEAP is quickly downregulated in response to ER stress. This phenomenon is observed in a wide range of cell types triggered by various ER stress inducers. The magnitude of the decrease in extracellular SEAP is proportional to the intensity of ER stress, which is inversely correlated with the induction of endogenous ER stress markers. In contrast to SEAP, the activity of intracellular luciferase is not affected by ER stress. ER stress causes a decrease in SEAP activity not via transcriptional suppression but via abnormal posttranslational modification, accelerated degradation, and reduced secretion of SEAP protein. In mice constitutively producing SEAP, in vivo induction of ER stress similarly causes rapid reduction in serum SEAP activity. Using SEAP as an indicator, real-time monitoring of ER stress in living cells and animals is feasible. The ESTRAP method provides a powerful tool to investigate the pathogenesis of ER stress-associated diseases, to assess toxicity and the adverse effects of drugs, and to develop therapeutic agents for the treatment of ER stress-related disorders.
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