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

Autor:	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., Kerr CH; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA., 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., Krishnarao PS; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA., Rosenblatt HD; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA., Raj N; Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA., Lantz TC; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA., Zhulyn O; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA., Bowen ME; Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA., Shokat L; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA., 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., 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., 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.
Jazyk:	angličtina
Zdroj:	Developmental cell [Dev Cell] 2021 Jul 26; Vol. 56 (14), pp. 2089-2102.e11. Date of Electronic Publication: 2021 Jul 08.
DOI:	10.1016/j.devcel.2021.06.013
Abstrakt:	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. Competing Interests: Declaration of interests D.R. is a shareholder of eFFECTOR Therapeutics and a member of its scientific advisory board. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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