Characterization of stanniocalcin 2, a novel target of the mammalian unfolded protein response with cytoprotective properties.
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.
Department of Neurobiology, Pharmacology, and Physiology, The University of Chicago, Knapp R212, 924 East 57th St., Chicago, IL 60637, USA.
Daisuke
D
Ito
John R
JR
Walker
Charlie S
CS
Thompson
Isabella
I
Moroz
William
W
Lin
Margaret L
ML
Veselits
Antoine M
AM
Hakim
Allen A
AA
Fienberg
Gopal
G
Thinakaran
D051696:Activating Transcription Factors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival; D006224:Cricetinae; D019610:Cytoprotection; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects; D017510:Protein Folding; D021381:Protein Transport; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
D051696:Activating Transcription Factors; D001798:Blood Proteins; D006023:Glycoproteins; D006861:Hydrogen Peroxide; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019284:Thapsigargin; D014157:Transcription Factors; D019892:eIF-2 Kinase; C485438:Stc2 protein, mouse