title: ATF5 regulates β-cell survival during stress.
abstract: The stress response and cell survival are necessary for normal pancreatic β-cell function, glucose homeostasis, and prevention of diabetes. The homeodomain transcription factor and human diabetes gene pancreas/duodenum homeobox protein 1 (Pdx1) regulates β-cell survival and endoplasmic reticulum stress susceptibility, in part through direct regulation of activating transcription factor 4 (Atf4). Here we show that Atf5, a close but less-studied relative of Atf4, is also a target of Pdx1 and is critical for β-cell survival under stress conditions. Pdx1 deficiency led to decreased Atf5 transcript, and primary islet ChIP-sequencing localized PDX1 to the Atf5 promoter, implicating Atf5 as a PDX1 target. Atf5 expression was stress inducible and enriched in β cells. Importantly, Atf5 deficiency decreased survival under stress conditions. Loss-of-function and chromatin occupancy experiments positioned Atf5 downstream of and parallel to Atf4 in the regulation of eIF4E-binding protein 1 (4ebp1), a mammalian target of rapamycin (mTOR) pathway component that inhibits protein translation. Accordingly, Atf5 deficiency attenuated stress suppression of global translation, likely enhancing the susceptibility of β cells to stress-induced apoptosis. Thus, we identify ATF5 as a member of the transcriptional network governing pancreatic β-cell survival during stress.
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.|Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Juliana
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.|Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Juxiang
authors.initials: J
authors.lastname: Yang
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.|Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Andrea V
authors.initials: AV
authors.lastname: Rozo
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.|Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Austin
authors.initials: A
authors.lastname: Good
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.|Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: David N
authors.initials: DN
authors.lastname: Groff
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605.|Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Shu-Zong
authors.initials: SZ
authors.lastname: Wang
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605; Michael.Green@umassmed.edu stoffers@mail.med.upenn.edu.|Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Michael R
authors.identifier: 0000-0003-3017-3298
authors.initials: MR
authors.lastname: Green
authors.affiliation: Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104; Michael.Green@umassmed.edu stoffers@mail.med.upenn.edu.|Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Doris A
authors.initials: DA
authors.lastname: Stoffers
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D051696:Activating Transcription Factors / Q000235:genetics* / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D039642:Eukaryotic Initiation Factors; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D051696:Activating Transcription Factors; D048868:Adaptor Proteins, Signal Transducing; C471855:Atf5 protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D018398:Homeodomain Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D051701:Activating Transcription Factor 4
keywords: 4EBP1; ATF5; apoptosis; pancreatic β cell; stress