A p53-dependent translational program directs tissue-selective phenotypes in a model of ribosomopathies.

Adaptor Proteins, Signal Transducing / genetics Animals Body Patterning Cell Cycle Proteins / genetics Extremities / embryology Gene Expression Regulation, Developmental Haploinsufficiency Mice Mice, Knockout Phenotype Protein Biosynthesis Protein Processing, Post-Translational Ribosomal Proteins / physiology Ribosomes / metabolism Tumor Suppressor Protein p53 / physiology
4E-BP1 limb development nucleolar stress p53 ribosomal protein haploinsufficiency ribosome profiling ribosomopathy translational control

Journal

Developmental cell
ISSN: 1878-1551
Titre abrégé: Dev Cell
Pays: United States
ID NLM: 101120028

Informations de publication

Date de publication:
26 07 2021
Historique:
received: 22 10 2020
revised: 26 03 2021
accepted: 11 06 2021
pubmed: 10 7 2021
medline: 10 11 2021
entrez: 9 7 2021
Statut: ppublish

Résumé

In ribosomopathies, perturbed expression of ribosome components leads to tissue-specific phenotypes. What accounts for such tissue-selective manifestations as a result of mutations in the ribosome, a ubiquitous cellular machine, has remained a mystery. Combining mouse genetics and in vivo ribosome profiling, we observe limb-patterning phenotypes in ribosomal protein (RP) haploinsufficient embryos, and we uncover selective translational changes of transcripts that controlling limb development. Surprisingly, both loss of p53, which is activated by RP haploinsufficiency, and augmented protein synthesis rescue these phenotypes. These findings are explained by the finding that p53 functions as a master regulator of protein synthesis, at least in part, through transcriptional activation of 4E-BP1. 4E-BP1, a key translational regulator, in turn, facilitates selective changes in the translatome downstream of p53, and this thereby explains how RP haploinsufficiency may elicit specificity to gene expression. These results provide an integrative model to help understand how in vivo tissue-specific phenotypes emerge in ribosomopathies.

Identifiants

DOI: 10.1016/j.devcel.2021.06.013 PMID: 34242585 PMC: PMC8319123
pubmed: 34242585
pii: S1534-5807(21)00520-7
doi: 10.1016/j.devcel.2021.06.013
pmc: PMC8319123
mid: NIHMS1717122
pii:
doi:

Substances chimiques

Adaptor Proteins, Signal Transducing 0
Cell Cycle Proteins 0
Eif4ebp1 protein, mouse 0
Ribosomal Proteins 0
Trp53 protein, mouse 0
Tumor Suppressor Protein p53 0

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

2089-2102.e11

Subventions

Organisme : NIDDK NIH HHS
ID : K08 DK119561
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD086634
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197591
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA242986
Pays : United States
Organisme : NICHD NIH HHS
ID : K12 HD072222
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007790
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA128583
Pays : United States

Informations de copyright

Copyright © 2021 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests D.R. is a shareholder of eFFECTOR Therapeutics and a member of its scientific advisory board.

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Auteurs

Gerald C Tiu (GC)

Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA; Stanford Medical Scientist Training Program, Stanford University, Stanford, CA 94305, USA.

Craig H Kerr (CH)

Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.

Craig M Forester (CM)

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Division of Pediatric Allergy, Immunology and Bone Marrow Transplantation, University of California, San Francisco, San Francisco, CA 94143, USA; Children's Hospital Colorado, Division of Pediatric Hematology/Oncology/Bone Marrow Transplant, Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

Pallavi S Krishnarao (PS)

Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.

Hannah D Rosenblatt (HD)

Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.

Nitin Raj (N)

Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Travis C Lantz (TC)

Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.

Olena Zhulyn (O)

Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.

Margot E Bowen (ME)

Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Leila Shokat (L)

Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.

Laura D Attardi (LD)

Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Davide Ruggero (D)

Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: davide.ruggero@ucsf.edu.

Maria Barna (M)

Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: mbarna@stanford.edu.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › A p53-dependent translational program directs...
questionsmedicales.fr › Eucaryotes › Animaux › A p53-dependent translational program directs...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Morphogenèse › Plan d'organisation du corps › A p53-dependent translational program directs...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines du cycle cellulaire › A p53-dependent translational program directs...
questionsmedicales.fr › Régions du corps › Membres › A p53-dependent translational program directs...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes au cours du développement › A p53-dependent translational program directs...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Dosage génique › Haploinsuffisance › A p53-dependent translational program directs...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › A p53-dependent translational program directs...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › A p53-dependent translational program directs...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › A p53-dependent translational program directs...
questionsmedicales.fr › Phénomènes génétiques › Expression des gènes › Biosynthèse des protéines › A p53-dependent translational program directs...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Modification traductionnelle des protéines › Maturation post-traductionnelle des protéines › A p53-dependent translational program directs...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines ribosomiques › A p53-dependent translational program directs...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Organites › Ribosomes › A p53-dependent translational program directs...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Phosphoprotéines › Protéine p53 suppresseur de tumeur › A p53-dependent translational program directs...