title: Transcriptional activator TAp63 is upregulated in muscular atrophy during ALS and induces the pro-atrophic ubiquitin ligase Trim63.
abstract: Mechanisms of muscle atrophy are complex and their understanding might help finding therapeutic solutions for pathologies such as amyotrophic lateral sclerosis (ALS). We meta-analyzed transcriptomic experiments of muscles of ALS patients and mouse models, uncovering a p53 deregulation as common denominator. We then characterized the induction of several p53 family members (p53, p63, p73) and a correlation between the levels of p53 family target genes and the severity of muscle atrophy in ALS patients and mice. In particular, we observed increased p63 protein levels in the fibers of atrophic muscles via denervation-dependent and -independent mechanisms. At a functional level, we demonstrated that TAp63 and p53 transactivate the promoter and increased the expression of Trim63 (MuRF1), an effector of muscle atrophy. Altogether, these results suggest a novel function for p63 as a contributor to muscular atrophic processes via the regulation of multiple genes, including the muscle atrophy gene Trim63.
authors.affiliation: UMR_S 1113, Molecular mechanisms of stress response and pathologies, Institut national de la santé et de la recherche médicale, Strasbourg, France.|Fédération de Recherche Translationnelle, Strasbourg University, Strasbourg, France.
authors.forename: Yannick
authors.identifier: http://orcid.org/0000-0003-2189-6953
authors.initials: Y
authors.lastname: von Grabowiecki
authors.affiliation: UMR_S 1113, Molecular mechanisms of stress response and pathologies, Institut national de la santé et de la recherche médicale, Strasbourg, France.|Fédération de Recherche Translationnelle, Strasbourg University, Strasbourg, France.
authors.forename: Paula
authors.initials: P
authors.lastname: Abreu
authors.affiliation: UMR_S 1113, Molecular mechanisms of stress response and pathologies, Institut national de la santé et de la recherche médicale, Strasbourg, France.|Fédération de Recherche Translationnelle, Strasbourg University, Strasbourg, France.
authors.forename: Orphee
authors.initials: O
authors.lastname: Blanchard
authors.affiliation: Fédération de Recherche Translationnelle, Strasbourg University, Strasbourg, France.|Sanford Burnham Medical Research Institute, San Diego, United States.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Palamiuc
authors.affiliation: Sanford Burnham Medical Research Institute, San Diego, United States.
authors.forename: Samir
authors.initials: S
authors.lastname: Benosman
authors.affiliation: Fédération de Recherche Translationnelle, Strasbourg University, Strasbourg, France.|Sanford Burnham Medical Research Institute, San Diego, United States.
authors.forename: Sophie
authors.initials: S
authors.lastname: Mériaux
authors.affiliation: UMR_S 1113, Molecular mechanisms of stress response and pathologies, Institut national de la santé et de la recherche médicale, Strasbourg, France.|Fédération de Recherche Translationnelle, Strasbourg University, Strasbourg, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Devignot
authors.affiliation: UMR_S 1113, Molecular mechanisms of stress response and pathologies, Institut national de la santé et de la recherche médicale, Strasbourg, France.|Fédération de Recherche Translationnelle, Strasbourg University, Strasbourg, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gross
authors.affiliation: UMR_S 1113, Molecular mechanisms of stress response and pathologies, Institut national de la santé et de la recherche médicale, Strasbourg, France.|Fédération de Recherche Translationnelle, Strasbourg University, Strasbourg, France.
authors.forename: Georg
authors.initials: G
authors.lastname: Mellitzer
authors.affiliation: Fédération de Recherche Translationnelle, Strasbourg University, Strasbourg, France.|Institut national de la santé et de la recherche médicale, Laboratoire SMN, Strasbourg, France.
authors.forename: José L
authors.initials: JL
authors.lastname: Gonzalez de Aguilar
authors.affiliation: UMR_S 1113, Molecular mechanisms of stress response and pathologies, Institut national de la santé et de la recherche médicale, Strasbourg, France.|Fédération de Recherche Translationnelle, Strasbourg University, Strasbourg, France.
authors.forename: Christian
authors.identifier: http://orcid.org/0000-0003-4315-3851
authors.initials: C
authors.lastname: Gaiddon
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D051379:Mice; D009124:Muscle Proteins / Q000096:biosynthesis*; D009132:Muscles / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis*; D000070584:Tripartite Motif Proteins; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis*; D015854:Up-Regulation
chemical_list: D009124:Muscle Proteins; C115051:TP63 protein, human; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C440908:TRIM63 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: ALS; cell biology; human; human biology; medicine; mouse; murf-1; muscle atrophy; p53; p63; trim63