Missense mutations in the TP53 (p53) gene have been linked to malignant progression. However, our in-silico analyses reveal that hepatocellular carcinoma (HCC) patients with mutant p53 (mutp53) have better overall survival compared to those with p53-null (p53) HCC, unlike other cancer types. Given the historical use of sorafenib (SOR) monotherapy for advanced HCC, we hypothesize that mutp53 increases sensitivity to SOR, a multikinase inhibitor that induces endoplasmic reticulum (ER) stress. Here we show that mutp53 inhibits stress granule (SG) formation by binding to an ER stress sensor, PKR-like ER kinase (PERK), and a key SG component, GAP SH3 domain-binding protein 1 (G3BP1), contributing to increased sensitivity of SG-competent cells and xenografts to ER stress inducers including SOR. Our study identifies a unique vulnerability imposed by mutp53, suggesting mutp53 as a biomarker for ER stress-inducing agents and highlighting the importance of SG inhibition for cancer treatment.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1038/s41467-025-57539-6 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Suppression of stress granule formation is a vulnerability imposed by mutant p53.
Nat Commun
March 2025
Department of Pediatrics, Division of Hematology & Oncology, Children's Mercy Research Institute, Kansas City, MO, USA.
Missense mutations in the TP53 (p53) gene have been linked to malignant progression. However, our in-silico analyses reveal that hepatocellular carcinoma (HCC) patients with mutant p53 (mutp53) have better overall survival compared to those with p53-null (p53) HCC, unlike other cancer types. Given the historical use of sorafenib (SOR) monotherapy for advanced HCC, we hypothesize that mutp53 increases sensitivity to SOR, a multikinase inhibitor that induces endoplasmic reticulum (ER) stress.
View Article and Find Full Text PDFAggregates associated with amyotrophic lateral sclerosis sequester the actin-binding protein profilin 2.
Hum Mol Genet
March 2025
Hannover Medical School, Institute of Neuroanatomy and Cell Biology, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease characterized by the degeneration of upper and lower motoneurons. The four most frequently mutated genes causing familial ALS (fALS) are C9orf72, FUS, SOD1, and TARDBP. Some of the related wild-type proteins comprise intrinsically disordered regions (IDRs) which favor their assembly in liquid droplets-the biophysical mechanism behind the formation of physiological granules such as stress granules (SGs).
View Article and Find Full Text PDFFission yeast Caprin protein is required for efficient heterochromatin establishment.
PLoS Genet
March 2025
Institute of Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.
Heterochromatin is a key feature of eukaryotic genomes that serves important regulatory and structural roles in regions such as centromeres. In fission yeast, maintenance of existing heterochromatic domains relies on positive feedback loops involving histone methylation and non-coding RNAs. However, requirements for de novo establishment of heterochromatin are less well understood.
View Article and Find Full Text PDFSelective serotonin reuptake inhibitors (SSRIs) are widely used to treat mood and anxiety disorders, yet their molecular mechanisms of action remain poorly understood. Here, we show that chronic treatment with the SSRI fluoxetine reinstates a developmental plasticity program in the dentate gyrus (DG) by remodeling the extracellular matrix (ECM). Fluoxetine elicited a robust transcriptomic response in the DG, where mature granule cells adopted a juvenile-like profile.
View Article and Find Full Text PDFCellular dsRNA interactome captured by K1 antibody reveals the regulatory map of exogenous RNA sensing.
Commun Biol
March 2025
Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.
RNA-binding proteins (RBPs) provide a critical post-transcriptional regulatory layer in determining RNA fate. Currently, UV crosslinking followed by oligo-dT pull-down is the gold standard in identifying the RBP repertoire of poly-adenylated RNAs, but such method is ineffective in capturing RBPs that recognize double-stranded RNAs (dsRNAs). Here, we utilize anti-dsRNA K1 antibody immunoprecipitation followed by quantitative mass spectrometry to comprehensively identify RBPs bound to cellular dsRNAs without external stimulus.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!