[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-374230-105":59,"doc-detail-374230-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","suppression-of-stress-granule-formation-is-a-vulnerability-imposed-by-mutant-p53","Suppression of stress granule formation is a vulnerability imposed by mutant p53","","Missense mutations in TP53 (mutant p53, mutp53) are linked to malignant progression, yet analysis of hepatocellular carcinoma (HCC) cohorts shows patients with mutp53 have better overall survival than those with p53-null tumors. Using in-silico, in vitro, and in vivo approaches, the study demonstrates that mutp53 suppresses stress granule (SG) formation by binding the ER stress sensor PERK and the SG component G3BP1. This SG inhibition increases sensitivity of SG-competent cells and xenografts to ER stress inducers, including sorafenib, identifying a mutp53-imposed vulnerability for targeted therapy.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/suppression-of-stress-granule-formation-is-a-vulnerability-imposed-by-mutant-p53/374230/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/suppression-of-stress-granule-formation-is-a-vulnerability-imposed-by-mutant-p53/374230.png","ImageObject",300,407,{"name":92,"@type":93},"Asher","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-24","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":29},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How do patients with mutant p53 (mutp53) compare to p53-null patients in overall survival for HCC?","Question",{"text":112,"@type":113},"For hepatocellular carcinoma, patients carrying missense mutp53 show better overall survival than those with p53-null HCC, unlike other cancer types.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What molecular interactions does mutp53 use to suppress stress granule (SG) formation?",{"text":117,"@type":113},"The study shows mutp53 binds the ER stress sensor PERK and the SG component G3BP1, inhibiting SG formation.",{"name":119,"@type":110,"acceptedAnswer":120},"How does SG inhibition relate to sensitivity to sorafenib (SOR)?",{"text":121,"@type":113},"By inhibiting stress granule formation under ER stress, mutp53 increases sensitivity of SG-competent cells and xenografts to ER stress inducers, including sorafenib.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},374230,1790730666,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":29,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},687197207639,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","Article [https://doi.org/10.1038/s41467-025-57539-6](https://doi.org/10.1038/s41467-025-57539-6)  \nSuppression of stress granule formation is a vulnerability imposed by mutant p53  \nReceived: 2 February 2024  \n\n| Accepted: 25 February 2025 |\n| --- |\n| |\n| Check for updates |\n\nElizabeth Thoenen 1, Atul Ranjan1, Alejandro Parrales1, Shigeto Nishikawa1, Dan A. Dixon2, Sugako Oka3 & Tomoo Iwakuma 1,4   \nMissense 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(p53null)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, PKRlike 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.  \nUnderstanding the mechanisms behind chemotherapy resistance is vital for improving current treatment strategies. Stress granules (SGs), cytoplasmic, liquid-liquid phase-separated, non-membranous cytoplasmic foci, consisting of ribonucleoprotein (RNP) and mRNAs, are implicated in chemotherapy resistance. SGs form when protein translation initiation is inhibited1. SGs enhance drug resistance in cancer by sequestering mRNAs or proteins involved in pro-death signaling, like TRAF2 and RACK12,3. SGs are also linked to cellular quiescence4. Moreover, inhibition of translation initiation, which triggers SG formation, can free up to 30% of cellular ATP, conserving cellular energy and promoting survival during genotoxic stress5. Additionally, phosphorylation of eukaryotic initiation factor 2α (eIF2α) uniquely enhances the translation of proteins like the transcription factor ATF4, promoting the mRNA expression of pro-survival genes involved in autophagy, amino acid metabolism, protein synthesis, and oxidative stress response6. However, little is known about SG regulation in cancer, and there are currently no strategies that leverage SG inhibition to increase the efficacy of cancer therapy.  \nTumor suppressor p53 is the most frequently mutated gene inhuman cancers (~50%), and the majority of p53 mutations are missense  \nmutations in the DNA binding domain7. Unlike other tumor suppressors, these missense mutations not only cause the loss ofwild-type p53 (wtp53) functions but also confer oncogenic gain-of-function (GOF) activities, independent of wtp53, that generally enhance malignant progression and drug resistance8,9. Clinically, p53 mutations are linked to cancer malignancy, metastasis, and therapy resistance10. Given its unique properties and high expression in cancers, missense mutant p53 (mutp53) is an ideal therapeutic target. However, directly targeting mutp53 itself has proven challenging11. One promising alternative strategy is to inhibit the signaling pathways or proteins modified by mutp53that are essential for cell survival12. Identifying and targeting these vulnerabilities could accelerate the development of novel and effective therapeutic strategies for tumors expressing mutp53.  \nOur in-silico analysis of The Cancer Genome Atlas (TCGA) dataset unexpectedly revealed that patients with hepatocellular carcinoma (HCC) carrying missense mutp53 had better overall survival compared to those with p53null HCC, distinct from other cancer types. While combination chemotherapies are commonly used to treat many cancers, advanced HCC has historically been treated ","cbCaiaJhZR5bXmLY","https://ap.wps.com/l/cbCaiaJhZR5bXmLY","pdf",6056502,17,"English","# Introduction\n# Results\n## The potential benefit of p53 mutations in HCC for increased SOR sensitivity","[{\"question\":\"How do patients with mutant p53 (mutp53) compare to p53-null patients in overall survival for HCC?\",\"answer\":\"For hepatocellular carcinoma, patients carrying missense mutp53 show better overall survival than those with p53-null HCC, unlike other cancer types.\"},{\"question\":\"What molecular interactions does mutp53 use to suppress stress granule (SG) formation?\",\"answer\":\"The study shows mutp53 binds the ER stress sensor PERK and the SG component G3BP1, inhibiting SG formation.\"},{\"question\":\"How does SG inhibition relate to sensitivity to sorafenib (SOR)?\",\"answer\":\"By inhibiting stress granule formation under ER stress, mutp53 increases sensitivity of SG-competent cells and xenografts to ER stress inducers, including sorafenib.\"}]","Suppression of stress granule formation is a vulnerability imposed by mutant p53 | PDF",1790201329,43]