دورية أكاديمية
أعرض في EDS

The spliceosome is a therapeutic vulnerability in MYC-driven cancer.

التفاصيل البيبلوغرافية
العنوان: The spliceosome is a therapeutic vulnerability in MYC-driven cancer.
المؤلفون: Hsu TY; Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.; Interdepartmental Program in Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, Texas 77030, USA.; Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA., Simon LM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA., Neill NJ; Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA., Marcotte R; Princess Margaret Cancer Centre, University Health Network, Toronto M5G 2C4, Canada., Sayad A; Princess Margaret Cancer Centre, University Health Network, Toronto M5G 2C4, Canada., Bland CS; Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA., Echeverria GV; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA., Sun T; Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA., Kurley SJ; Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA., Tyagi S; Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA., Karlin KL; Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA., Dominguez-Vidaña R; Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.; Interdepartmental Program in Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA., Hartman JD; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA., Renwick A; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA., Scorsone K; Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA., Bernardi RJ; Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA., Skinner SO; Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Physics, University of Illinois, Urbana, Illinois 61801, USA., Jain A; Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA., Orellana M; Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA., Lagisetti C; Center for Chemical Biology, Bioscience Division, SRI International, Menlo Park, California 94025, USA., Golding I; Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Physics, University of Illinois, Urbana, Illinois 61801, USA., Jung SY; Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA., Neilson JR; Interdepartmental Program in Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA., Zhang XH; The Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas 77030, USA., Cooper TA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA., Webb TR; Center for Chemical Biology, Bioscience Division, SRI International, Menlo Park, California 94025, USA., Neel BG; Princess Margaret Cancer Centre, University Health Network, Toronto M5G 2C4, Canada.; Department of Medical Biophysics, University of Toronto, Toronto M5S 2J7, Canada., Shaw CA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA., Westbrook TF; Verna &Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.; Interdepartmental Program in Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
المصدر: Nature [Nature] 2015 Sep 17; Vol. 525 (7569), pp. 384-8. Date of Electronic Publication: 2015 Sep 02.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE
أسماء مطبوعة: Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.
مواضيع طبية MeSH: Breast Neoplasms/*drug therapy , Breast Neoplasms/*genetics , Genes, myc/*genetics , Spliceosomes/*drug effects , Spliceosomes/*metabolism, Animals ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Survival/drug effects ; Cell Transformation, Neoplastic/drug effects ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; HeLa Cells ; Humans ; Introns/genetics ; Mice ; Mice, Nude ; Neoplasm Metastasis/drug therapy ; Nuclear Proteins/metabolism ; Phosphoproteins/metabolism ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; RNA Precursors/biosynthesis ; RNA Precursors/genetics ; RNA Splicing/drug effects ; RNA Splicing Factors ; RNA, Messenger/biosynthesis ; RNA, Messenger/genetics ; Ribonucleoprotein, U2 Small Nuclear/metabolism ; Ribonucleoproteins/metabolism ; Splicing Factor U2AF ; Xenograft Model Antitumor Assays
مستخلص: MYC (also known as c-MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. MYC is a transcription factor, and many of its pro-tumorigenic functions have been attributed to its ability to regulate gene expression programs. Notably, oncogenic MYC activation has also been shown to increase total RNA and protein production in many tissue and disease contexts. While such increases in RNA and protein production may endow cancer cells with pro-tumour hallmarks, this increase in synthesis may also generate new or heightened burden on MYC-driven cancer cells to process these macromolecules properly. Here we discover that the spliceosome is a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene in human mammary epithelial cells, and demonstrate that BUD31 is a component of the core spliceosome required for its assembly and catalytic activity. Core spliceosomal factors (such as SF3B1 and U2AF1) associated with BUD31 are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total precursor messenger RNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Notably, genetic or pharmacological inhibition of the spliceosome in vivo impairs survival, tumorigenicity and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing, and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers.
التعليقات: Comment in: Nat Rev Cancer. 2015 Oct;15(10):574-5. (PMID: 26383137)
Comment in: Cancer Cell. 2015 Oct 12;28(4):405-6. (PMID: 26461086)
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معلومات مُعتمدة: R01 CA140474 United States CA NCI NIH HHS; R01 CA178039 United States CA NCI NIH HHS; F30 CA180447 United States CA NCI NIH HHS; R25 GM056929 United States GM NIGMS NIH HHS; P30 AI036211 United States AI NIAID NIH HHS; 1R01CA178039-01 United States CA NCI NIH HHS; S10 RR024574 United States RR NCRR NIH HHS; U54 CA149196 United States CA NCI NIH HHS; R01 GM082837 United States GM NIGMS NIH HHS; 1F30CA180447 United States CA NCI NIH HHS; R01 AR045653 United States AR NIAMS NIH HHS; P30CA125123 United States CA NCI NIH HHS; R01 CA190467 United States CA NCI NIH HHS; U54-CA149196 United States CA NCI NIH HHS; R01 AR060733 United States AR NIAMS NIH HHS; P30 CA125123 United States CA NCI NIH HHS; R21 CA185769 United States CA NCI NIH HHS; R01 HL045565 United States HL NHLBI NIH HHS
سلسلة جزيئية: GEO GSE66182
المشرفين على المادة: 0 (BUD31 protein, human)
0 (Nuclear Proteins)
0 (Phosphoproteins)
0 (Proto-Oncogene Proteins c-myc)
0 (RNA Precursors)
0 (RNA Splicing Factors)
0 (RNA, Messenger)
0 (Ribonucleoprotein, U2 Small Nuclear)
0 (Ribonucleoproteins)
0 (SF3B1 protein, human)
0 (Splicing Factor U2AF)
0 (U2AF1 protein, human)
تواريخ الأحداث: Date Created: 20150903 Date Completed: 20151014 Latest Revision: 20220317
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC4831063
DOI: 10.1038/nature14985
PMID: 26331541
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-4687
DOI:10.1038/nature14985