ArticlePloS one2009
Regulation of PERK signaling and leukemic cell survival by a novel cytosolic isoform of the UPR regulator GRP78/BiP.
Article in PloS one, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
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Who cites it
89 citing papers in PubMed, 156 citations in OpenAlex.
- RNF5 promotes acute lung injury through HSPA5 ER-to-cytosol translocation and resultant PERK activation.Cell death and differentiation · 2026Article
- Mechanism of sinomenine-induced apoptosis of human liver cancer cells via GRP78 membrane translocation.Molecular biology reports · 2026Article
- Surface Proteomic Analysis Reveals the Presence of Noncanonical Cell Membrane Endoplasmic Reticulum Chaperones in High-Grade Gliomas.Journal of proteome research · 2026Article
- Cardiomyocyte-derived USP20 mitigates myocardial ischemia/reperfusion injury through deubiquitinating GRP78.Theranostics · 2026Article
- Enhancing Cytosolic Internalization of [International journal of molecular sciences · 2025Article
- Article
- Stress-induced translocation of the endoplasmic reticulum chaperone GRP78/BiP and its impact on human disease and therapy.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Cancer-Targeting Peptides Functionalized With Polyarginine Enables GRP78-Dependent Cell Uptake and siRNA Delivery Within the DU145 Prostate Cancer Cells.Journal of peptide science : an official publication of the European Peptide Society · 2025Article
- Targeting stress induction of GRP78 by cardiac glycoside oleandrin dually suppresses cancer and COVID-19.Cell & bioscience · 2024Article
- Duck Tembusu virus NS3 protein induces apoptosis by activating the PERK/PKR pathway and mitochondrial pathway.Journal of virology · 2023Article
- Combination of RUNX1 inhibitor and gemcitabine mitigates chemo-resistance in pancreatic ductal adenocarcinoma by modulating BiP/PERK/eIF2α-axis-mediated endoplasmic reticulum stress.Journal of experimental & clinical cancer research : CR · 2023Article
- Plasmodesmal endoplasmic reticulum proteins regulate intercellular trafficking of cucumber mosaic virus in Arabidopsis.Journal of experimental botany · 2023Article
- ER chaperone GRP78/BiP translocates to the nucleus under stress and acts as a transcriptional regulator.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Endoplasmic Reticulum Stress in Renal Cell Carcinoma.International journal of molecular sciences · 2023Review
- Endoplasmic Reticulum Stress and Cancer: Could Unfolded Protein Response Be a Druggable Target for Cancer Therapy?International journal of molecular sciences · 2023Review
- Resveratrol promotes liver cell survival in mice liver-induced ischemia-reperfusion through unfolded protein response: a possible approach in liver transplantation.BMC pharmacology & toxicology · 2022Article
- Decoy receptor 2 mediates the apoptosis-resistant phenotype of senescent renal tubular cells and accelerates renal fibrosis in diabetic nephropathy.Cell death & disease · 2022Article
- HSP70 and HSP90 in Cancer: Cytosolic, Endoplasmic Reticulum and Mitochondrial Chaperones of Tumorigenesis.Frontiers in oncology · 2022Review
- Combined analysis of the transcriptome and proteome ofFrontiers in chemistry · 2022Article
- Suppression of ER-stress induction of GRP78 as an anti-neoplastic mechanism of the cardiac glycoside Lanatoside C in pancreatic cancer: Lanatoside C suppresses GRP78 stress induction.Neoplasia (New York, N.Y.) · 2021Article
29 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The unfolded protein response (UPR) is an evolutionarily conserved mechanism to allow cells to adapt to stress targeting the endoplasmic reticulum (ER). Induction of ER chaperone GRP78/BiP increases protein folding capacity; as such it represents a major survival arm of UPR. Considering the central importance of the UPR in regulating cell survival and death, evidence is emerging that cells evolve feedback regulatory pathways to modulate the key UPR executors, however, the precise mechanisms remain to be elucidated. Here, we report the fortuitous discovery of GRP78va, a novel isoform of GRP78 generated by alternative splicing (retention of intron 1) and alternative translation initiation. Bioinformatic and biochemical analyses revealed that expression of GRP78va is enhanced by ER stress and is notably elevated in human leukemic cells and leukemia patients. In contrast to the canonical GRP78 which is primarily an ER lumenal protein, GRP78va is devoid of the ER signaling peptide and is cytosolic. Through specific knockdown of endogenous GRP78va by siRNA without affecting canonical GRP78, we showed that GRP78va promotes cell survival under ER stress. We further demonstrated that GRP78va has the ability to regulate PERK signaling and that GRP78va is able to interact with and antagonize PERK inhibitor P58(IPK). Our study describes the discovery of GRP78va, a novel cytosolic isoform of GRP78/BiP, and the first characterization of the modulation of UPR signaling via alternative splicing of nuclear pre-mRNA. Our study further reveals a novel survival mechanism in leukemic cells and other cell types where GRP78va is expressed.
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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.