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Mol. Cell. Biol. 24 (21): 9456-9469

Copyright © 2004 by the American Society for Microbiology. All rights reserved.

Characterization of Stanniocalcin 2, a Novel Target of the Mammalian Unfolded Protein Response with Cytoprotective Properties

Daisuke Ito,1 John R. Walker,2 Charlie S. Thompson,3 Isabella Moroz,3 William Lin,4 Margaret L. Veselits,1 Antoine M. Hakim,3 Allen A. Fienberg,2, and Gopal Thinakaran1,4*

Department of Neurobiology, Pharmacology, and Physiology,1 Committee on Neurobiology, The University of Chicago, Chicago, Illinois,4 Genomics Institute of the Novartis Research Foundation, San Diego, California,2 Neuroscience Research Program, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada3

Received for publication 17 March 2004. Revision received 20 April 2004. Accepted for publication 10 August 2004.

Abstract: Accumulation of misfolded proteins in the endoplasmic reticulum (ER) induces a highly conserved homeostatic response in all eukaryotic cells, termed the unfolded-protein response (UPR). Here we describe the characterization of stanniocalcin 2 (STC2), a mammalian homologue of a calcium- and phosphate-regulating hormone first identified in fish, as a novel target of the UPR. Expression of STC2 gene is rapidly upregulated in cultured cells after exposure to tunicamycin and thapsigargin, by ATF4 after activation of the ER-resident kinase PERK. In addition, STC2 expression is also activated in neuronal cells by oxidative stress and hypoxia but not by several cellular stresses unrelated to the UPR. In contrast, expression of another homologue, STC1, is only upregulated by hypoxia independent of PERK or ATF4 expression. In vivo studies revealed that rat cortical neurons rapidly upregulate STC2 after transient middle cerebral artery occlusion. Finally, siRNA-mediated inhibition of STC2 expression renders N2a neuroblastoma cells and HeLa cells significantly more vulnerable to apoptotic cell death after treatment with thapsigargin, and overexpression of STC2 attenuated thapsigargin-induced cell death. Consequently, induced STC2 expression is an essential feature of survival component of the UPR.

* Corresponding author. Mailing address: Department of Neurobiology, Pharmacology, and Physiology, The University of Chicago, Knapp R212, 924 East 57th St., Chicago, IL 60637. Phone: (773) 834-3752. Fax: (773) 834-3808. E-mail: gopal{at}uchicago.edu.

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