title: Serum- and glucocorticoid-induced protein kinase 1 (SGK1) is regulated by store-operated Ca2+ entry and mediates cytoprotection against necrotic cell death.
abstract: Serum and glucocorticoid-regulated kinase 1 (SGK1) encodes a phosphatidylinositol 3-kinase-dependent serine/threonine kinase that is rapidly induced in response to cellular stressors and is an important cell survival signal. Previous studies have suggested that an increase in cytoplasmic Ca(2+) concentration ([Ca(2+)]c) is required for increased SGK1 expression, but the subcellular source of Ca(2+) regulating SGK1 transcription remains uncertain. Activation of endoplasmic reticulum stress (ERS) with thapsigargin (TG) increased SGK1 mRNA and protein expression in MDA-MB-231 cells. Intracellular Ca(2+) imaging revealed that store-operated Ca(2+) entry played a prominent role in SGK1 induction by TG. Neither ERS nor release of Ca(2+) from the ER was sufficient to activate SGK1. Prolonged elevation of intracellular Ca(2+) levels, however, triggered cell death with a much greater proportion of the cells undergoing necrosis rather than apoptosis. A relative increase in the percentage of cells undergoing necrosis was observed in cells expressing a short hairpin RNA targeted to the SGK1 gene. Necrotic cell death evoked by cytoplasmic Ca(2+) overloading was associated with persistent hyperpolarization of the inner mitochondrial membrane and a modest increase in calpain activation, but did not involve detectable caspase 3 or caspase 7 activation. The effects of cytoplasmic Ca(2+) overloading on mitochondrial membrane potential were significantly reduced in cells expressing SGK1 compared with SGK1-depleted cells. Our findings indicate that store-operated Ca(2+) entry regulates SGK1 expression in epithelial cells and suggest that SGK1-dependent cytoprotective signaling involves effects on maintaining mitochondrial function.
authors.affiliation: From the Sections of Hematology/Oncology.
authors.forename: Deanna R
authors.initials: DR
authors.lastname: Brickley
authors.affiliation: From the Sections of Hematology/Oncology.
authors.forename: Abena S
authors.initials: AS
authors.lastname: Agyeman
authors.affiliation: the Departments of Medicine.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kopp
authors.affiliation: From the Sections of Hematology/Oncology.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Hall
authors.affiliation: Endocrinology, Department of Medicine.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Harbeck
authors.affiliation: From the Sections of Hematology/Oncology.
authors.forename: Larissa
authors.initials: L
authors.lastname: Belova
authors.affiliation: From the Sections of Hematology/Oncology.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Volden
authors.affiliation: From the Sections of Hematology/Oncology.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: the Departments of Medicine; Cell and Developmental Biology, The State University of New York Upstate Medical University, Syracuse, New York 13210. Electronic address: roem@upstate.edu.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Roe
authors.affiliation: From the Sections of Hematology/Oncology; Ben May Department for Cancer Biology, The University of Chicago, Chicago, Illinois 60637. Electronic address: sdconzen@uchicago.edu.
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Conzen
mesh_terms: D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004790:Enzyme Induction / Q000235:genetics; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D005260:Female; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000473:pathology; D009336:Necrosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D002118:Calcium; D053148:Caspase 3; D053179:Caspase 7; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases; C505407:CASP3 protein, human; C505520:CASP7 protein, human
keywords: Apoptosis; Calcium Signaling; Cytoprotection; Mitochondrial Apoptosis; Mitochondrial Membrane Potential; Necrosis (Necrotic Death); SGK1; Signal Transduction
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