Editors' ChoiceStress responses

Tolerating ER Stress

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Science's STKE  26 Oct 2004:
Vol. 2004, Issue 256, pp. tw384
DOI: 10.1126/stke.2562004tw384

Cells monitor how well synthesis of new proteins in the endoplasmic reticulum (ER) is going, and when stressful conditions cause accumulation of unfolded proteins, the unfolded protein response (UPR) is initiated, which signals for appropriate changes in cellular systems. Ito et al. used a microarray screen to detect genes whose products were specifically expressed in response to agents that cause ER stress. They identified stanniocalcin2 (STC2), which is related to a hormone originally described in fish that functions to prevent hypercalcemia. Expression of STC2 was increased in cultured cells undergoing the UPR after exposure to thapsigargin, an inhibitor of the sarco(endo)plasmic reticulum Ca2+-ATPase. Like other UPR genes, STC2 was also expressed in rat brain tissue after transient cerebral ischemia. Expression of STC2 appears to require signaling from the PERK serine-threonine kinase, a known mediator of the UPR, to the transcription factor ATF4, because mouse embryo fibroblasts lacking PERK or ATF4 failed to increase expression of STC2. Treatment of N2a neuroblastoma cells or HeLa cells with siRNA to inhibit STC2 expression increased apoptosis of those cells when treated with thapsigargin. Conversely, overexpression of STC2 in HeLa cells reduced the percentage of cells undergoing apoptosis after thapsigargin treatment. Increased synthesis of STC2, which was detected in the ER by immunofluoresence microscopy and was also secreted from cells undergoing ER stress, appears to contribute to signaling mechanisms that help protect cells under certain stressful conditions.

D. Ito, J. R. Walker, C. S. Thompson, I. Moroz, W. Lin, M. L. Veselits, A. M. Hakim, A. A. Fienberg, G. Thinakaran, Characterization of stanniocalcin 2, a novel target of the mammalian unfolded protein response with cytoprotective properties. Mol. Cell. Biol. 24, 9456-9469 (2004). [Abstract] [Full Text]

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