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

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.

This study was supported by grants from the National Institutes of Health and the Brain Research Foundation (G.T.) and from the Sankyo Life Science Foundation (D.I.).

We are grateful to David Ron (Skirball Institute, New York University) for providing IRE1β and PERK cDNAs and PERK^−/− fibroblasts, Linda M. Hendershot (St. Jude Children's Research Hospital, Memphis, Tenn.) for providing ATF4^−/− fibroblasts, Laurie H. Glimcher (Harvard School of Public Health, Boston, Mass.) for providing XBP-1^−/− fibroblasts, and T. Y. Chang (Dartmouth Medical School, Hanover, N.H.) for providing the S2P-deficient CHO cells. We thank Manuel F. Utset (University of Chicago) for discussions and advice on histology.