Unfolded protein response (UPR) integrated signaling networks determine cell fate during hypoxia

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Abstract

During hypoxic conditions, cells undergo critical adaptive responses that include the up-regulation of hypoxia-inducible proteins (HIFs) and the induction of the unfolded protein response (UPR). While their induced signaling pathways have many distinct targets, there are some important connections as well. Despite the extensive studies on both of these signaling pathways, the exact mechanisms involved that determine survival versus apoptosis remain largely unexplained and therefore beyond therapeutic control. Here we discuss the complex relationship between the HIF and UPR signaling pathways and the importance of understanding how these pathways differ between normal and cancer cell models.

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Most cited references 221

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HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.

M Ivan, K Kondo, H. Yang … (2001)

HIF (hypoxia-inducible factor) is a transcription factor that plays a pivotal role in cellular adaptation to changes in oxygen availability. In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the von Hippel-Lindau tumor suppressor protein (pVHL). We found that human pVHL binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and Fe(2+), this protein modification may play a key role in mammalian oxygen sensing.

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ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.

Jin Ye, Robert Rawson, Ryutaro Komuro … (2000)

ATF6 is a membrane-bound transcription factor that activates genes in the endoplasmic reticulum (ER) stress response. When unfolded proteins accumulate in the ER, ATF6 is cleaved to release its cytoplasmic domain, which enters the nucleus. Here, we show that ATF6 is processed by Site-1 protease (S1P) and Site-2 protease (S2P), the enzymes that process SREBPs in response to cholesterol deprivation. ATF6 processing was blocked completely in cells lacking S2P and partially in cells lacking S1P. ATF6 processing required the RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively. Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress. ATF6 processing did not require SCAP, which is essential for SREBP processing. We conclude that S1P and S2P are required for the ER stress response as well as for lipid synthesis.

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A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation.

G. L. Semenza, G. L. Wang (1992)

We have identified a 50-nucleotide enhancer from the human erythropoietin gene 3'-flanking sequence which can mediate a sevenfold transcriptional induction in response to hypoxia when cloned 3' to a simian virus 40 promoter-chloramphenicol acetyltransferase reporter gene and transiently expressed in Hep3B cells. Nucleotides (nt) 1 to 33 of this sequence mediate sevenfold induction of reporter gene expression when present in two tandem copies compared with threefold induction when present in a single copy, suggesting that nt 34 to 50 bind a factor which amplifies the induction signal. DNase I footprinting demonstrated binding of a constitutive nuclear factor to nt 26 to 48. Mutagenesis studies revealed that nt 4 to 12 and 19 to 23 are essential for induction, as substitutions at either site eliminated hypoxia-induced expression. Electrophoretic mobility shift assays identified a nuclear factor which bound to a probe spanning nt 1 to 18 but not to a probe containing a mutation which eliminated enhancer function. Factor binding was induced by hypoxia, and its induction was sensitive to cycloheximide treatment. We have thus defined a functionally tripartite, 50-nt hypoxia-inducible enhancer which binds several nuclear factors, one of which is induced by hypoxia via de novo protein synthesis.

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Author and article information

Contributors

Sylwia Bartoszewska: sylwiabart@gumed.edu.pl

James F. Collawn: jcollawn@uab.edu

Journal

Journal ID (nlm-ta): Cell Mol Biol Lett

Journal ID (iso-abbrev): Cell. Mol. Biol. Lett

Title: Cellular & Molecular Biology Letters

Publisher: BioMed Central (London )

ISSN (Print): 1425-8153

ISSN (Electronic): 1689-1392

Publication date (Electronic): 13 March 2020

Publication date PMC-release: 13 March 2020

Publication date Collection: 2020

Volume: 25

Electronic Location Identifier: 18

Affiliations

[1 ]GRID grid.11451.30, ISNI 0000 0001 0531 3426, Department of Inorganic Chemistry, , Medical University of Gdansk, ; Gdansk, Poland

[2 ]GRID grid.265892.2, ISNI 0000000106344187, Department of Cell, Developmental and Integrative Biology, , University of Alabama at Birmingham, ; Birmingham, USA

Article

Publisher ID: 212

DOI: 10.1186/s11658-020-00212-1

PMC ID: 7071609

PubMed ID: 32190062

SO-VID: 9d49e1ca-eed4-4434-ac19-53236df72951

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 7 November 2019

Date accepted : 26 February 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004281, Narodowe Centrum Nauki;

Award ID: UMO-2015/17/B/NZ3/01485

Award ID: 2015/18/E/NZ3/00687

Award Recipient : Sylwia Bartoszewska

Funded by: FundRef http://dx.doi.org/10.13039/100000897, Cystic Fibrosis Foundation;

Award ID: ROWE15R0

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: P30 DK072482

Custom metadata

Keywords: er-stress,angiogenesis,hypoxia-reoxygenation injury,ischemia,cell fate determination,uprmt

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Keywords: er-stress, angiogenesis, hypoxia-reoxygenation injury, ischemia, cell fate determination, uprmt

Unfolded protein response (UPR) integrated signaling networks determine cell fate during hypoxia

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Neuronal Signaling

Most cited references 221

HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing.

ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.

A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation.

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