title: TRIB3 enhances cell viability during glucose deprivation in HEK293-derived cells by upregulating IGFBP2, a novel nutrient deficiency survival factor.
abstract: Glucose deprivation occurs in several human diseases, including infarctions and solid tumors, and leads to cell death. In this article, we investigate the role of the pseudokinase Tribbles homolog 3 (TRIB3) in the cellular stress response to glucose starvation using cell lines derived from HEK293, which is highly glycolytic under standard conditions. Our results show that TRIB3 mRNA and protein levels are strongly upregulated in glucose-deprived cells via the induction of activating transcription factor 4 (ATF4) by the endoplasmic reticulum (ER) stress sensor kinase PERK. Cell survival in glucose-deficient conditions is enhanced by TRIB3 overexpression and reduced by TRIB3 knockdown. Genome-wide gene expression profiling uncovered approximately 40 glucose deprivation-responsive genes that are affected by TRIB3, including several genes involved in signaling processes and metabolism. Based on transcription factor motif analysis, the majority of TRIB3-downregulated genes are target genes of ATF4, which TRIB3 is known to inhibit. The gene most substantially upregulated by TRIB3 is insulin-like growth factor binding protein 2 (IGFBP2). IGFBP2 mRNA and protein levels are downregulated in cells subjected to glucose deprivation, and reduced IGFBP2 expression aggravates cell death during glucose deficiency, while overexpression of IGFBP2 prolongs cell survival. Moreover, IGFBP2 silencing abrogates the pro-survival effect of TRIB3. Since TRIB3 augments IGFBP2 expression in glucose-starved cells, the data indicate that IGFBP2 contributes to the attenuation of cell death by TRIB3. These results implicate TRIB3 and IGFBP2, both of which are known to be overexpressed in several types of cancers, as pro-survival modulators of cell viability in nutrient-deficient microenvironments.
authors.affiliation: Estonian Biocentre, Riia 23b, 51010 Tartu, Estonia; Institute of Molecular and Cell Biology, University of Tartu, Riia 23, 51010 Tartu, Estonia.
authors.forename: Tiit
authors.initials: T
authors.lastname: Örd
authors.affiliation: Estonian Biocentre, Riia 23b, 51010 Tartu, Estonia.
authors.forename: Daima
authors.initials: D
authors.lastname: Örd
authors.affiliation: Institute of Computer Science, University of Tartu, Liivi 2, 50409 Tartu, Estonia.
authors.forename: Priit
authors.initials: P
authors.lastname: Adler
authors.affiliation: Institute of Computer Science, University of Tartu, Liivi 2, 50409 Tartu, Estonia.
authors.forename: Jaak
authors.initials: J
authors.lastname: Vilo
authors.affiliation: Estonian Biocentre, Riia 23b, 51010 Tartu, Estonia. Electronic address: tord@ebc.ee.
authors.forename: Tõnis
authors.initials: T
authors.lastname: Örd
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000235:genetics; D015854:Up-Regulation; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: C497109:ATF4 protein, human; D018797:Cell Cycle Proteins; C577903:IGFBP2 protein, human; D018971:Insulin-Like Growth Factor Binding Protein 2; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C474831:TRIB3 protein, human; D051701:Activating Transcription Factor 4; C460640:EIF2AK3 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D005947:Glucose
keywords: Cell death; Gene expression; Glucose deprivation; IGFBP2; TRB3; Tribbles