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Media type:
E-Article
Title:
ATF5 regulates β-cell survival during stress
Contributor:
Juliana, Christine A.;
Yang, Juxiang;
Rozo, Andrea V.;
Good, Austin;
Groff, David N.;
Wang, Shu-Zong;
Green, Michael R.;
Stoffers, Doris A.
imprint:
National Academy of Sciences, 2017
Published in:Proceedings of the National Academy of Sciences of the United States of America
Language:
English
ISSN:
1091-6490;
0027-8424
Origination:
Footnote:
Description:
<p>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 (<italic>Pdx1</italic>) regulates β-cell survival and endoplasmic reticulum stress susceptibility, in part through direct regulation of activating transcription factor 4 (<italic>Atf4</italic>). Here we show that <italic>Atf5</italic>, a close but less-studied relative of <italic>Atf4</italic>, is also a target of Pdx1 and is critical for β-cell survival under stress conditions. <italic>Pdx1</italic> deficiency led to decreased <italic>Atf5</italic> transcript, and primary islet ChIP-sequencing localized PDX1 to the <italic>Atf5</italic> promoter, implicating <italic>Atf5</italic> as a PDX1 target. <italic>Atf5</italic> expression was stress inducible and enriched in β cells. Importantly, <italic>Atf5</italic> 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 (<italic>4ebp1</italic>), a mammalian target of rapamycin (mTOR) pathway component that inhibits protein translation. Accordingly, <italic>Atf5</italic> 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.</p>