title: Selective dysfunction of p53 for mitochondrial biogenesis induces cellular proliferation in bronchial smooth muscle from asthmatic patients.
abstract: Increase of bronchial smooth muscle (BSM) mass is a crucial feature of asthma remodeling. The mechanisms of such an increased BSM mass are complex but involve enhanced mitochondrial biogenesis, leading to increased proliferation of BSM cells in asthmatic patients. The major tumor suppressor protein p53 is a key cell regulator involved in cell proliferation and has also been implicated in mitochondrial biogenesis. However, the role of p53 in BSM cell proliferation and mitochondrial biogenesis has not been investigated thus far.
  
  
  
  We sought to evaluate the role of p53 in proliferation of BSM cells in asthmatic patients and mitochondrial biogenesis.
  
  
  
  The expression of p53 was assessed both in vitro by using flow cytometry and Western blotting and ex vivo by using RT-PCR after laser microdissection. The role of p53 was assessed with small hairpin RNA lentivirus in both asthmatic patients and control subjects with BSM cell proliferation by using 5-bromo-2'-deoxyuridine and cell counting and in the expression of p21, BCL2-associated X protein, mitochondrial transcription factor A (TFAM), and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α).
  
  
  
  Twenty-nine patients with moderate-to-severe asthma and 26 control subjects were enrolled in the study. p53 expression was increased in BSM from asthmatic patients both ex vivo and in vitro, with a decreased interaction with mouse double minute 2 homolog (Mdm2) and an increased phosphorylation of serine 20. p53 did not inhibit the transcription of both TFAM and PGC-1α in BSM cells from asthmatic patients. As a consequence, p53 is unable to slow the increased mitochondrial biogenesis and hence the subsequent increased proliferation of BSM cells in asthmatic patients.
  
  
  
  This study suggests that p53 might act as a new potential therapeutic target against BSM remodeling in asthmatic patients.
authors.affiliation: Université Bordeaux, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Département de Pharmacologie, Bordeaux, France; INSERM, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Bordeaux, France. Electronic address: thomas.trian@u-bordeaux.fr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Trian
authors.affiliation: Université Bordeaux, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Département de Pharmacologie, Bordeaux, France; INSERM, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Bordeaux, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Allard
authors.affiliation: Université Bordeaux, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Département de Pharmacologie, Bordeaux, France; INSERM, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Bordeaux, France; CHU de Bordeaux, Service d'Exploration Fonctionnelle Respiratoire, Service de chirurgie thoracique, Service d'anatomopathologie, Pessac, France.
authors.forename: Annaig
authors.initials: A
authors.lastname: Ozier
authors.affiliation: Université Bordeaux, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Département de Pharmacologie, Bordeaux, France; INSERM, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Bordeaux, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Maurat
authors.affiliation: Université Bordeaux, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Département de Pharmacologie, Bordeaux, France; INSERM, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Bordeaux, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dupin
authors.affiliation: Université Bordeaux, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Département de Pharmacologie, Bordeaux, France; INSERM, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Bordeaux, France; CHU de Bordeaux, Service d'Exploration Fonctionnelle Respiratoire, Service de chirurgie thoracique, Service d'anatomopathologie, Pessac, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Thumerel
authors.affiliation: Université Bordeaux, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Département de Pharmacologie, Bordeaux, France; INSERM, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Bordeaux, France.
authors.forename: Olga
authors.initials: O
authors.lastname: Ousova
authors.affiliation: Université Bordeaux, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Département de Pharmacologie, Bordeaux, France; INSERM, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Bordeaux, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gillibert-Duplantier
authors.affiliation: Institut Bergonié de Bordeaux, Unité Inserm VINCO, Bordeaux, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Le Morvan
authors.affiliation: CHU de Bordeaux, Service d'Exploration Fonctionnelle Respiratoire, Service de chirurgie thoracique, Service d'anatomopathologie, Pessac, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Begueret
authors.affiliation: Université Bordeaux, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Département de Pharmacologie, Bordeaux, France; INSERM, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Bordeaux, France; CHU de Bordeaux, Service d'Exploration Fonctionnelle Respiratoire, Service de chirurgie thoracique, Service d'anatomopathologie, Pessac, France.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Girodet
authors.affiliation: Université Bordeaux, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Département de Pharmacologie, Bordeaux, France; INSERM, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Bordeaux, France; CHU de Bordeaux, Service d'Exploration Fonctionnelle Respiratoire, Service de chirurgie thoracique, Service d'anatomopathologie, Pessac, France.
authors.forename: Roger
authors.initials: R
authors.lastname: Marthan
authors.affiliation: Université Bordeaux, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Département de Pharmacologie, Bordeaux, France; INSERM, Centre de Recherche Cardio-thoracique de Bordeaux, U1045, Bordeaux, France; CHU de Bordeaux, Service d'Exploration Fonctionnelle Respiratoire, Service de chirurgie thoracique, Service d'anatomopathologie, Pessac, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Berger
mesh_terms: D000328:Adult; D000368:Aged; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D001980:Bronchi / Q000378:metabolism*; D016022:Case-Control Studies; D049109:Cell Proliferation; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D009130:Muscle, Smooth / Q000378:metabolism*; D001678:Organelle Biogenesis; D012129:Respiratory Function Tests; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D018927:Anti-Asthmatic Agents; D016159:Tumor Suppressor Protein p53
keywords: Asthma; lentivirus; mitochondrial transcription factor A; peroxisome proliferator-activated receptor γ coactivator 1α; remodeling