Selective dysfunction of p53 for mitochondrial biogenesis induces cellular proliferation in bronchial smooth muscle from asthmatic patients - 03/06/16
, Benoit Allard, PhD a, b, Annaig Ozier, MD, PhD a, b, c, Elise Maurat a, b, Isabelle Dupin, PhD a, b, Matthieu Thumerel, MD a, b, c, Olga Ousova, PhD a, b, Jennifer Gillibert-Duplantier, PhD a, b, Valérie Le Morvan, PhD d, Hugues Begueret, MD, PhD c, Pierre-Olivier Girodet, MD, PhD a, b, c, Roger Marthan, MD, PhD a, b, c, Patrick Berger, MD, PhD a, b, cAbstract |
Background |
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.
Objective |
We sought to evaluate the role of p53 in proliferation of BSM cells in asthmatic patients and mitochondrial biogenesis.
Methods |
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).
Results |
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.
Conclusion |
This study suggests that p53 might act as a new potential therapeutic target against BSM remodeling in asthmatic patients.
Le texte complet de cet article est disponible en PDF.Key words : Asthma, remodeling, lentivirus, peroxisome proliferator-activated receptor γ coactivator 1α, mitochondrial transcription factor A
Abbreviations used : Bax, BrdU, BSM, DMEM, FITC, GFP, Mdm2, PGC-1α, shRNA, α-SMA, TFAM, TOM 20
Plan
| Supported by grants from the Agence Nationale de la Recherche (no. 2010 CESA 001 01 [2010-0145] and ANR-12-BSV1-0023-03). T.T. was funded by the Agence Nationale de la Recherche (no. 2010 CESA 001 01 [2010-0145]). |
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| Disclosure of potential conflict of interest: B. Allard, A. Ozier, E. Maurat, I. Dupin, O. Ousova, J. Gillibert-Duplantier, and H. Begueret have received research support from Agence Nationale de la Recherche. T. Trian, P.-O. Girodet, and R. Marthan have received research support from Agence Nationale de la Recherche and has a pending US patent (US no. 12/487,273; ie, bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma). P. Berger has received research support from Agence Nationale de la Recherche, GlaxoSmithKline, and Pierre Fabre; is on the boards for Novartis, GlaxoSmithKline, and Boehringer Ingelheim; has provided expert testimony for AstraZeneca; has received lecture fees from Novartis, GlaxoSmithKline, Chiesi, AstraZeneca, and Takeda; has a pending US patent (US no. 12/487,273; ie, bronchial smooth muscle remodeling involves calcium-dependent enhanced mitochondrial biogenesis in asthma); and has received travel support from Takeda, Chiesi, Boehringer Ingelheim, Novartis, and GlaxoSmithKline. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 137 - N° 6
P. 1717 - juin 2016 Retour au numéro
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