ArticlePLoS genetics2014
Fine tuning of the UPR by the ubiquitin ligases Siah1/2.
Article in PLoS genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 40 citations in OpenAlex.
- Links between the unfolded protein response and the DNA damage response in hypoxia: a systematic review.Biochemical Society transactions · 2021Pooled it
- Mitochondrial Fusion and Fission in Age-Related Cardio-Cerebral Diseases: Mechanisms and Interventions.Aging cell · 2026Review
- Ubiquitin and ubiquitin-like modifications in the endoplasmic reticulum stress response.The FEBS journal · 2026Review
- Liposome-Polymer Nanoparticles Loaded with Copper Diethyldithiocarbamate and 6-Bromo-Indirubin-3'-Oxime Enable the Treatment of Refractive Melanoma.Small (Weinheim an der Bergstrasse, Germany) · 2025Article
- Disordered regions in the IRE1α ER lumenal domain mediate its stress-induced clustering.The EMBO journal · 2024Article
- The Role of Ubiquitin-Proteasome System and Mitophagy in the Pathogenesis of Parkinson's Disease.Neuromolecular medicine · 2023Review
- Ubiquitin Ligases Siah1a/2 Control Alveolar Macrophage Functions to Limit Carcinogen-Induced Lung Adenocarcinoma.Cancer research · 2023Article
- HMGB1-induced activation of ER stress contributes to pulmonary artery hypertension in vitro and in vivo.Respiratory research · 2023Article
- Upregulation of ATF4-LAMP3 Axis by ORF45 Facilitates Lytic Replication of Kaposi's Sarcoma-Associated Herpesvirus.Journal of virology · 2022Article
- Historical perspective and progress on protein ubiquitination at glutamatergic synapses.Neuropharmacology · 2021Review
- PML/RARA destabilization by hyperthermia: a new model for oncogenic fusion protein degradation?Blood cancer discovery · 2021Article
- Siah2 control of T-regulatory cells limits anti-tumor immunity.Nature communications · 2020Article
- The E3 Ubiquitin Ligase SIAH1 Targets MyD88 for Proteasomal Degradation During Dengue Virus Infection.Frontiers in microbiology · 2020Article
- Review
- Identification and characterization of small molecule inhibitors of the ubiquitin ligases Siah1/2 in melanoma and prostate cancer cells.Cancer letters · 2019Article
- Crosstalk Between Hypoxia and ER Stress Response: A Key Regulator of Macrophage Polarization.Frontiers in immunology · 2019Review
- Ubiquitin ligases in oncogenic transformation and cancer therapy.Nature reviews. Cancer · 2018Review
- Crosstalk Between Mammalian Autophagy and the Ubiquitin-Proteasome System.Frontiers in cell and developmental biology · 2018Review
- The E3 ubiquitin ligase Siah1 regulates adrenal gland organization and aldosterone secretion.JCI insight · 2017Article
- Adaptive preconditioning in neurological diseases - therapeutic insights from proteostatic perturbations.Brain research · 2016Review
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
The endoplasmic reticulum (ER) responds to changes in intracellular homeostasis through activation of the unfolded protein response (UPR). Yet, it is not known how UPR-signaling coordinates adaptation versus cell death. Previous studies suggested that signaling through PERK/ATF4 is required for cell death. We show that high levels of ER stress (i.e., ischemia-like conditions) induce transcription of the ubiquitin ligases Siah1/2 through the UPR transducers PERK/ATF4 and IRE1/sXBP1. In turn, Siah1/2 attenuates proline hydroxylation of ATF4, resulting in its stabilization, thereby augmenting ER stress output. Conversely, ATF4 activation is reduced upon Siah1/2 KD in cultured cells, which attenuates ER stress-induced cell death. Notably, Siah1a(+/-)::Siah2(-/-) mice subjected to neuronal ischemia exhibited smaller infarct volume and were protected from ischemia-induced death, compared with the wild type (WT) mice. In all, Siah1/2 constitutes an obligatory fine-tuning mechanism that predisposes cells to death under severe ER stress conditions.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.