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, siRNAmediated 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.

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“…1C and Dataset S3). Moreover, of the two exceptions, STC2 has also been reported to be an ATF4-induced gene in another study (29). To confirm these results, we interrogated the expression of a panel of ER-stress-induced genes upon treatment with Nelfinavir.…”

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“…The UPR has three branches, each acting via separate transcription factor represented by ATF4, ATF6, and XBP1 (20). The blue module contained large number of ER chaperones, which are known to be regulated primarily by XBP1, whereas many of the red module UPR genes (SLC7A5, ATF4, and STC2) are known targets of ATF4 (18,19,21). This finding suggests that differences in transcriptional regulatory mechanisms may underlie separation of genes into modules.…”

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“…STC2 is an antagonist of FSHstimulated progesterone production in granulosa cells (Lou et al, 2005) and inhibits the sodium-phosphate transporters, NaPi-3, in the kidney (Ishibashi et al, 1998). In addition, STC2 is involved in cell survival during oxidative stress and hypoxia (Ito et al, 2004). Transgenic mice over-expressing STC2 display dramatic growth retardation in almost every organ and tissue type with the exception of the testes which are identical in weight to wild-type male mice at birth (Gagliardi et al, 2005).…”