Altered RNA Splicing by Mutant p53 Activates Oncogenic RAS Signaling in Pancreatic Cancer.

Animals Carcinoma, Pancreatic Ductal / genetics Cell Line, Tumor Cells, Cultured Female Gene Expression Regulation, Neoplastic Humans Kaplan-Meier Estimate Mice, Inbred C57BL Mice, Knockout Mutation Pancreatic Neoplasms / genetics Proto-Oncogene Proteins p21(ras) / genetics RNA Splicing RNAi Therapeutics / methods Signal Transduction / genetics Tumor Suppressor Protein p53 / genetics Xenograft Model Antitumor Assays / methods
GAP17 GTPase signaling KRAS RNA splicing SF3B1 hnRNPK oncogenes p53 pancreatic cancer splicing inhibitors

Journal

Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617

Informations de publication

Date de publication:
10 08 2020
Historique:
received: 26 08 2019
revised: 17 01 2020
accepted: 11 05 2020
pubmed: 20 6 2020
medline: 9 3 2021
entrez: 20 6 2020
Statut: ppublish

Résumé

Pancreatic ductal adenocarcinoma (PDAC) is driven by co-existing mutations in KRAS and TP53. However, how these mutations collaborate to promote this cancer is unknown. Here, we uncover sequence-specific changes in RNA splicing enforced by mutant p53 which enhance KRAS activity. Mutant p53 increases expression of splicing regulator hnRNPK to promote inclusion of cytosine-rich exons within GTPase-activating proteins (GAPs), negative regulators of RAS family members. Mutant p53-enforced GAP isoforms lose cell membrane association, leading to heightened KRAS activity. Preventing cytosine-rich exon inclusion in mutant KRAS/p53 PDACs decreases tumor growth. Moreover, mutant p53 PDACs are sensitized to inhibition of splicing via spliceosome inhibitors. These data provide insight into co-enrichment of KRAS and p53 mutations and therapeutics targeting this mechanism in PDAC.

Identifiants

DOI: 10.1016/j.ccell.2020.05.010 PMID: 32559497 PMC: PMC8028848
pubmed: 32559497
pii: S1535-6108(20)30260-9
doi: 10.1016/j.ccell.2020.05.010
pmc: PMC8028848
mid: NIHMS1676183
pii:
doi:

Substances chimiques

KRAS protein, human 0
TP53 protein, human 0
Tumor Suppressor Protein p53 0
Proto-Oncogene Proteins p21(ras) EC 3.6.5.2

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

198-211.e8

Subventions

Organisme : NCI NIH HHS
ID : R35 CA232113
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA226342
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL128239
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA023108
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA087497
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL069768
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA013106
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204228
Pays : United States
Organisme : NCI NIH HHS
ID : K08 CA218420
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA226342
Pays : United States

Informations de copyright

Copyright © 2020. Published by Elsevier Inc.

Déclaration de conflit d'intérêts

Declaration of Interests L.F.E.-H. is a consultant for KDx Diagnostics Inc and OncoGenesis Inc. O.A.-W. served as a consultant for H3B Biomedicine, Foundation Medicine Inc, Merck, and Janssen, and is on the scientific advisory board of Envisagenics; O.A.-W. received prior research funding from H3B Biomedicine unrelated to the current manuscript and serves on the Scientific Advisory Board of Envisagenics Inc. S.D.L. is a member of the Scientific Advisory Board for Nybo Pharmaceuticals and co-founder of Episteme Prognostics.

Références

Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12408-15
pubmed: 8618911
Cell. 2018 Jan 25;172(3):578-589.e17
pubmed: 29373830
Cancer Cell. 2012 Sep 11;22(3):304-17
pubmed: 22975374
Int J Biol Sci. 2016 Jan 28;12(3):338-46
pubmed: 26929740
Nature. 1992 Sep 10;359(6391):153-4
pubmed: 1522900
Cancer Res. 2006 Jan 1;66(1):242-7
pubmed: 16397237
Nucleic Acids Res. 2016 Jul 8;44(W1):W90-7
pubmed: 27141961
Mol Cell. 2018 Jun 7;70(5):854-867.e9
pubmed: 29883606
Nat Methods. 2017 Jul;14(7):687-690
pubmed: 28581496
Cancer Cell. 2015 May 11;27(5):617-30
pubmed: 25965569
Nat Struct Mol Biol. 2012 Jan 15;19(2):220-8
pubmed: 22245967
Gastroenterology. 2013 Jun;144(6):1220-9
pubmed: 23622131
Nat Rev Cancer. 2010 Dec;10(12):842-57
pubmed: 21102635
Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10380-5
pubmed: 15240889
Mol Cancer Res. 2015 Sep;13(9):1325-35
pubmed: 26037647
Mol Cell Biol. 1993 Apr;13(4):2420-31
pubmed: 8455619
Cell Signal. 2013 Jan;25(1):236-46
pubmed: 22975681
Methods. 2005 Oct;37(2):183-89
pubmed: 16288887
Cancer Cell. 2010 Nov 16;18(5):448-58
pubmed: 21075310
Genome Biol. 2014;15(12):550
pubmed: 25516281
Nat Biotechnol. 2016 May;34(5):525-7
pubmed: 27043002
Cancer Cell. 2005 May;7(5):469-83
pubmed: 15894267
Cell Signal. 2014 Sep;26(9):1975-84
pubmed: 24703939
Chin Clin Oncol. 2017 Jun;6(3):24
pubmed: 28705001
J Biol Chem. 2011 Dec 9;286(49):42248-42256
pubmed: 22021035
Nat Med. 2016 Sep 7;22(9):976-86
pubmed: 27603132
Z Med Phys. 2009;19(3):200-6
pubmed: 19761098
Nature. 2016 Mar 3;531(7592):47-52
pubmed: 26909576
Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):246-51
pubmed: 20018721
Clin Cancer Res. 2017 Jan 15;23(2):336-341
pubmed: 27836865
J Cell Biol. 2009 Nov 2;187(3):375-84
pubmed: 19948481
Cell. 2015 Jan 15;160(1-2):324-38
pubmed: 25557080
Nat Protoc. 2008;3(6):1101-8
pubmed: 18546601
J Cell Sci. 2010 Apr 15;123(Pt 8):1295-305
pubmed: 20332115
Nat Biotechnol. 2011 Jan;29(1):79-83
pubmed: 21131983
Nat Genet. 2015 Oct;47(10):1168-78
pubmed: 26343385
Annu Rev Cancer Biol. 2019 Mar;3(1):167-185
pubmed: 32864546
Nat Med. 2018 May;24(4):497-504
pubmed: 29457796
Cell. 2014 Apr 10;157(2):382-394
pubmed: 24725405
Nat Rev Cancer. 2016 Jul;16(7):413-30
pubmed: 27282250
Genome Biol. 2018 Mar 23;19(1):40
pubmed: 29571299
Nature. 2015 Sep 17;525(7569):384-8
pubmed: 26331541
Cell. 2004 Dec 17;119(6):847-60
pubmed: 15607980
BMC Bioinformatics. 2015 Jul 19;16:224
pubmed: 26187896
Cold Spring Harb Perspect Med. 2018 Aug 1;8(8):
pubmed: 29101114
Nat Med. 2011 Apr;17(4):500-3
pubmed: 21460848
Int J Cancer. 2012 Aug 1;131(3):582-90
pubmed: 22015967
FEBS Lett. 2004 Nov 5;577(1-2):134-40
pubmed: 15527774
Nucleic Acids Res. 2007;35(6):e43
pubmed: 17311810
Nucleic Acids Res. 2011 May;39(9):3529-42
pubmed: 21245042
Nature. 1989 Dec 7;342(6250):711-4
pubmed: 2480526
Ann Surg Oncol. 2010 Oct;17(10):2619-27
pubmed: 20499280
Cell. 2006 Jan 13;124(1):207-19
pubmed: 16413492
Mol Ther. 2017 May 3;25(5):1069-1075
pubmed: 28366767
Br J Cancer. 2006 Oct 9;95(7):921-7
pubmed: 16953238
Methods Enzymol. 2006;407:703-10
pubmed: 16757363
Nucleic Acids Res. 2009 Jul;37(Web Server issue):W202-8
pubmed: 19458158
Adv Biol Regul. 2014 May;55:1-14
pubmed: 24814062
J Mol Diagn. 2015 May;17(3):251-64
pubmed: 25801821
Leukemia. 2019 Feb;33(2):390-402
pubmed: 30038380

Auteurs

Luisa F Escobar-Hoyos (LF)

David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Therapeutic Radiology, Yale University, School of Medicine, New Haven, CT 06520, USA; Department of Biology, Research Group Genetic Toxicology and Cytogenetics, School of Natural Sciences and Education, Universidad del Cauca, Popayán, Colombia; Department of Pathology, Renaissance School of Medicine, Stony Brook University, New York, NY 11794, USA. Electronic address: luisa.escobar-hoyos@yale.edu.

Alex Penson (A)

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Marie-José and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Ram Kannan (R)

Howard Hughes Medical Institute, Cancer Biology & Genetics Program, Sloan-Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Hana Cho (H)

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Chun-Hao Pan (CH)

Department of Pathology, Renaissance School of Medicine, Stony Brook University, New York, NY 11794, USA.

Rohit K Singh (RK)

Institute of Biochemistry, University of Münster, Münster, Germany.

Lisa H Apken (LH)

Institute of Molecular Tumor Biology, University of Münster, Münster, Germany.

G Aaron Hobbs (GA)

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Renhe Luo (R)

Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Nicolas Lecomte (N)

David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Sruthi Babu (S)

Department of Pathology, Renaissance School of Medicine, Stony Brook University, New York, NY 11794, USA.

Fong Cheng Pan (FC)

David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Direna Alonso-Curbelo (D)

David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Marie-José and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

John P Morris (JP)

David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Marie-José and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Gokce Askan (G)

David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Olivera Grbovic-Huezo (O)

David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Marie-José and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Paul Ogrodowski (P)

Howard Hughes Medical Institute, Cancer Biology & Genetics Program, Sloan-Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Jonathan Bermeo (J)

David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Joseph Saglimbeni (J)

David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Cristian D Cruz (CD)

David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Yu-Jui Ho (YJ)

Howard Hughes Medical Institute, Cancer Biology & Genetics Program, Sloan-Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Sharon A Lawrence (SA)

David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Jerry P Melchor (JP)

David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Grant A Goda (GA)

Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Karen Bai (K)

Department of Pathology, Renaissance School of Medicine, Stony Brook University, New York, NY 11794, USA.

Alessandro Pastore (A)

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Simon J Hogg (SJ)

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Srivatsan Raghavan (S)

Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Peter Bailey (P)

Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110, Heidelberg, Baden-Württemberg 69120, Germany; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, G61 1Q, Glasgow, UK.

David K Chang (DK)

The Kinghorn Cancer Centre, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia; Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, NSW, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, NSW, Australia.

Andrew Biankin (A)

Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110, Heidelberg, Baden-Württemberg 69120, Germany; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, G61 1Q, Glasgow, UK; The Kinghorn Cancer Centre, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia; Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, NSW, Australia.

Kenneth R Shroyer (KR)

Department of Pathology, Renaissance School of Medicine, Stony Brook University, New York, NY 11794, USA.

Brian M Wolpin (BM)

Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.

Andrew J Aguirre (AJ)

Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

Andrea Ventura (A)

Howard Hughes Medical Institute, Cancer Biology & Genetics Program, Sloan-Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Barry Taylor (B)

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Marie-José and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Departments of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Channing J Der (CJ)

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Daniel Dominguez (D)

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Daniel Kümmel (D)

Institute of Biochemistry, University of Münster, Münster, Germany.

Andrea Oeckinghaus (A)

Institute of Molecular Tumor Biology, University of Münster, Münster, Germany.

Scott W Lowe (SW)

David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, Cancer Biology & Genetics Program, Sloan-Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.

Robert K Bradley (RK)

Fred Hutchinson Cancer Research Center Seattle, Seattle, WA 98109-1024, USA.

Omar Abdel-Wahab (O)

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Steven D Leach (SD)

David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Dartmouth Norris Cotton Cancer Center, Lebanon, NH 03766, USA. Electronic address: steven.d.leach@dartmouth.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Altered RNA Splicing by Mutant p53 Activates...
questionsmedicales.fr › Maladies endocriniennes › Tumeurs des glandes endocrines › Tumeurs du pancréas › Carcinome du canal pancréatique › Altered RNA Splicing by Mutant p53 Activates...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Altered RNA Splicing by Mutant p53 Activates...
questionsmedicales.fr › Cellules › Cellules cultivées › Altered RNA Splicing by Mutant p53 Activates...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Altered RNA Splicing by Mutant p53 Activates...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Altered RNA Splicing by Mutant p53 Activates...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Analyse de survie › Estimation de Kaplan-Meier › Altered RNA Splicing by Mutant p53 Activates...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Altered RNA Splicing by Mutant p53 Activates...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › Altered RNA Splicing by Mutant p53 Activates...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Altered RNA Splicing by Mutant p53 Activates...
questionsmedicales.fr › Maladies endocriniennes › Tumeurs des glandes endocrines › Tumeurs du pancréas › Altered RNA Splicing by Mutant p53 Activates...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes p21(ras) › Altered RNA Splicing by Mutant p53 Activates...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Maturation post-transcriptionnelle des ARN › Épissage des ARN › Altered RNA Splicing by Mutant p53 Activates...
questionsmedicales.fr › Thérapeutique › Biothérapie › Thérapie par l'interférence par ARN › Altered RNA Splicing by Mutant p53 Activates...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Altered RNA Splicing by Mutant p53 Activates...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Phosphoprotéines › Protéine p53 suppresseur de tumeur › Altered RNA Splicing by Mutant p53 Activates...
questionsmedicales.fr › Techniques d'investigation › Transplantation tumorale › Tests d'activité antitumorale sur modèle de xénogreffe › Altered RNA Splicing by Mutant p53 Activates...