Stanniocalcin 2 Is a Negative Modulator of Store-Operated Calcium Entry

Zeiger, William; Ito, Daisuke; McGinley, Marisa; Oh‐hora, Masatsugu; Villereal, Mitchel L.; Wang, Shuai

doi:10.1128/mcb.05140-11

Cited by 61 publications

(61 citation statements)

References 64 publications

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“…2), in keeping with previous observations (Park et al, 2005;Wu et al, 2007). Although the work by Wu et al (2007) associated the receptor's protective function with phosphatidylinositol 3-OH kinase-Akt/ protein kinase B activation, a recent study suggested that Stc2 provided cell protection by negatively regulating intracellular store-operated calcium entry, thus limiting the free Ca 21 concentration necessary for initiation of apoptosis (Zeiger et al, 2011). Consequently, the AhR may influence multiple signaling pathways conducive to cell survival.…”

Section: Ahr-driven Stc2 Expression Confers Cytoprotectionsupporting

confidence: 59%

Aryl Hydrocarbon Receptor–Dependent Stanniocalcin 2 Induction by Cinnabarinic Acid Provides Cytoprotection against Endoplasmic Reticulum and Oxidative Stress

Joshi

Carter

Harper

et al. 2015

J Pharmacol Exp Ther

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The aryl hydrocarbon receptor (AhR) is a cytosolic ligandactivated transcription factor historically known for its role in xenobiotic metabolism. Although AhR activity has previously been shown to play a cytoprotective role against intrinsic apoptotic stimuli, the underlying mechanism by which AhR confers cytoprotection against apoptosis is largely unknown. Here, we demonstrate that activation of AhR by the tryptophan catabolite cinnabarinic acid (CA) directly upregulates expression of stanniocalcin 2 (Stc2) to elicit cytoprotection against apoptosis induced by endoplasmic reticulum stress and oxidative stress. Chromatin immunoprecipitation studies demonstrated that CA treatment induces direct AhR binding to a region of the Stc2 promoter containing multiple xenobiotic response elements. Using isolated primary hepatocytes from AhR wild-type (AhR floxed) and liver-specific AhR conditional knockout mice, we showed that pretreatment with CA conferred cytoprotection against hydrogen peroxide (H 2 O 2 )-, thapsigargin-, and ethanolinduced apoptosis in an AhR-dependent manner. Furthermore, suppressing Stc2 expression using RNA interference confirmed that the cytoprotective properties of CA against H 2 O 2 , thapsigargin, and ethanol injury were absolutely dependent on Stc2. Immunochemistry revealed the presence of Stc2 in the endoplasmic reticulum and on the cell surface, consistent with Stc2 secretion and autocrine and/or paracrine signaling. Finally, in vivo data using a mouse model of acute alcohol hepatotoxicity demonstrated that CA provided cytoprotection against ethanolinduced apoptosis, hepatic microvesicular steatosis, and liver injury. Collectively, our data uncovered a novel mechanism for AhR-mediated cytoprotection in the liver that is dependent on CA-induced Stc2 activity.

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Section: Ahr-driven Stc2 Expression Confers Cytoprotectionsupporting

confidence: 59%

Aryl Hydrocarbon Receptor–Dependent Stanniocalcin 2 Induction by Cinnabarinic Acid Provides Cytoprotection against Endoplasmic Reticulum and Oxidative Stress

Joshi

Carter

Harper

et al. 2015

J Pharmacol Exp Ther

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“…Because disruption of ER function and Ca 2ϩ signaling can result in ER stress and subsequent activation of the unfolded protein response, it is possible that STIM1 may also contribute to the regulation of the ER stress response. In support of this, Stanniocalcin 2 (Stc), an ER stress protein, has been shown to colocalize with STIM1 and decreased Stc expression led to increased SOCE, whereas increased Stc levels attenuated SOCE (146). In addition, the ER stress protein ERp57 has been shown to interact with STIM1 and modulate SOCE (94).…”

Section: Orai1/trpcmentioning

confidence: 99%

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

Collins

Zhu-Mauldin

Marchase

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

110

102

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Collins HE, Zhu-Mauldin X, Marchase RB, Chatham JC. STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology. Am J Physiol Heart Circ Physiol 305: H446 -H458, 2013. First published June 21, 2013 doi:10.1152/ajpheart.00104.2013.-Store-operated Ca 2ϩ entry (SOCE) is critical for Ca 2ϩ signaling in nonexcitable cells; however, its role in the regulation of cardiomyocyte Ca 2ϩ homeostasis has only recently been investigated. The increased understanding of the role of stromal interaction molecule 1 (STIM1) in regulating SOCE combined with recent studies demonstrating the presence of STIM1 in cardiomyocytes provides support that this pathway co-exists in the heart with the more widely recognized Ca 2ϩ handling pathways associated with excitation-contraction coupling. There is now substantial evidence that STIM1-mediated SOCE plays a key role in mediating cardiomyocyte hypertrophy, both in vitro and in vivo, and there is growing support for the contribution of SOCE to Ca 2ϩ overload associated with ischemia/reperfusion injury. Here, we provide an overview of our current understanding of the molecular regulation of SOCE and discuss the evidence supporting the role of STIM1/Orai1-mediated SOCE in regulating cardiomyocyte function.store-operated Ca 2ϩ entry; stromal interaction molecule 1; orai1; cardiomyocytes STORE-OPERATED CA 2ϩ ENTRY (SOCE), also known as capacitative calcium entry (CCE), is the major mechanism of Ca 2ϩ entry in nearly all nonexcitable cells (97, 99). In addition, it is increasingly recognized to co-exist with voltage-gated Ca 2ϩ channels in excitable cells, including neurons, skeletal muscle cells, and cardiomyocytes (1,38,45,83,121). In response to inositol 1,4,5-triphosphate (IP 3 )-(43) or ryanodine receptor (RyR)-mediated (3) Ca 2ϩ release from ER/SR stores, SOCE facilitates the influx of Ca 2ϩ from the extracellular space, resulting in a sustained increase in cytosolic Ca 2ϩ levels. Thus, although one of the roles of SOCE is to rapidly refill the depleted ER/SR stores, the subsequent sustained increase in cytosolic Ca 2ϩ also regulates numerous gene transcription pathways (33,50,151). Indeed, aberrant SOCE has been observed in a growing number of diseases including severe combined immunodeficiency, acute pancreatitis, and Alzheimer's disease (86).The integration of SOCE into well-established models of Ca 2ϩ homeostasis was hampered for many years by the lack of specific molecular mediators; even as recently as 2004 there was considerable controversy as to the specific mechanisms regulating SOCE (90, 113). However, in 2005, stromal interaction molecule 1 (STIM1) was found to localize to the ER/SR membrane and shown to function as a primary mediator of SOCE (54, 102). The putative physiological and pathophysiological roles of SOCE and STIM1 that have been identified to date are summarized in Table 1. A number of studies have recently reported the presence of STIM1 in adult cardiomyocytes (37,59,153), and consistent with earlier evidence supporting a rol...

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“…The pMX-C99 -6myc plasmid has been previously described (34). Rabbit polyclonal antisera against STIM1, APP, PS1, and Flotillin-2 were previously generated in our laboratory and have been described (35)(36)(37)(38). The following antibodies were purchased: anti-Nicastrin (Santa Cruz), mAb 9E10 (ATCC), anti-protein disulfide isomerase (Stressgen), and mAb 4G8 (Covance).…”

Section: Methodsmentioning

confidence: 99%

Ca2+ Influx through Store-operated Ca2+ Channels Reduces Alzheimer Disease β-Amyloid Peptide Secretion

Zeiger

Vetrivel

Buggia-Prévot

et al. 2013

Journal of Biological Chemistry

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Stanniocalcin 2 Is a Negative Modulator of Store-Operated Calcium Entry

Cited by 61 publications

References 64 publications

Aryl Hydrocarbon Receptor–Dependent Stanniocalcin 2 Induction by Cinnabarinic Acid Provides Cytoprotection against Endoplasmic Reticulum and Oxidative Stress

Aryl Hydrocarbon Receptor–Dependent Stanniocalcin 2 Induction by Cinnabarinic Acid Provides Cytoprotection against Endoplasmic Reticulum and Oxidative Stress

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

Ca2+ Influx through Store-operated Ca2+ Channels Reduces Alzheimer Disease β-Amyloid Peptide Secretion

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