dc.contributor.author | Dalton, WB | |
dc.contributor.author | Helmenstine, E | |
dc.contributor.author | Walsh, N | |
dc.contributor.author | Gondek, LP | |
dc.contributor.author | Kelkar, DS | |
dc.contributor.author | Read, A | |
dc.contributor.author | Natrajan, R | |
dc.contributor.author | Christenson, ES | |
dc.contributor.author | Roman, B | |
dc.contributor.author | Das, S | |
dc.contributor.author | Zhao, L | |
dc.contributor.author | Leone, RD | |
dc.contributor.author | Shinn, D | |
dc.contributor.author | Groginski, T | |
dc.contributor.author | Madugundu, AK | |
dc.contributor.author | Patil, A | |
dc.contributor.author | Zabransky, DJ | |
dc.contributor.author | Medford, A | |
dc.contributor.author | Lee, J | |
dc.contributor.author | Cole, AJ | |
dc.contributor.author | Rosen, M | |
dc.contributor.author | Thakar, M | |
dc.contributor.author | Ambinder, A | |
dc.contributor.author | Donaldson, J | |
dc.contributor.author | DeZern, AE | |
dc.contributor.author | Cravero, K | |
dc.contributor.author | Chu, D | |
dc.contributor.author | Madero-Marroquin, R | |
dc.contributor.author | Pandey, A | |
dc.contributor.author | Hurley, PJ | |
dc.contributor.author | Lauring, J | |
dc.contributor.author | Park, BH | |
dc.date.accessioned | 2020-05-28T11:48:50Z | |
dc.date.issued | 2019-08-08 | |
dc.identifier.citation | The Journal of clinical investigation, 2019, 129 (11), pp. 4708 - 4723 | |
dc.identifier.issn | 0021-9738 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3654 | |
dc.identifier.eissn | 1558-8238 | |
dc.identifier.doi | 10.1172/jci125022 | |
dc.description.abstract | Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of SF3B1MUT xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against SF3B1MUT cancers. | |
dc.format | Electronic | |
dc.format.extent | 4708 - 4723 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER SOC CLINICAL INVESTIGATION INC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Neoplasms | |
dc.subject | Serine | |
dc.subject | Glycine | |
dc.subject | Neoplasm Proteins | |
dc.subject | Phosphoproteins | |
dc.subject | Proteome | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Energy Metabolism | |
dc.subject | Mutation | |
dc.subject | Phosphoglycerate Dehydrogenase | |
dc.subject | Transcriptome | |
dc.subject | Cellular Reprogramming | |
dc.subject | RNA Splicing Factors | |
dc.title | Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation. | |
dc.type | Journal Article | |
rioxxterms.versionofrecord | 10.1172/jci125022 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2019-08-08 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | The Journal of clinical investigation | |
pubs.issue | 11 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/17/18 Starting Cohort | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genomics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Functional Genomics | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/17/18 Starting Cohort | |
pubs.publication-status | Published | |
pubs.volume | 129 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Functional Genomics | |
dc.contributor.icrauthor | Read, Abigail | |
dc.contributor.icrauthor | Natrajan, Rachael | |