Prostaglandin EP2 receptor signaling protects human trabecular meshwork cells from apoptosis induced by ER stress through down-regulation of p53

Autor: Georges Kalouche, Annick Coste, Cécile Orsini, Thomas Debeir, William Rostène, Céline Boucher, Xavier Vigé, Christophe Baudouin, Laurent Debussche
Přispěvatelé: Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sanofi Research & Development - Translational Sciences Unit, Sanofi Research & Development - Oncology, Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Sanofi Research & Development - Ophthalmology, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), HAL-UPMC, Gestionnaire
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
p53
Apoptosis
trabecular meshwork cells
Cyclic AMP
Guanine Nucleotide Exchange Factors
Receptor
Endoplasmic Reticulum Chaperone BiP
Heat-Shock Proteins
Cell Death
Tunicamycin
Cytochromes c
Endoplasmic Reticulum Stress
Mitochondria
3. Good health
Cell biology
Caspases
Prostaglandin EP2 receptor
Signal transduction
ER stress
Signal Transduction
EP2 receptor
Adult
Agonist
medicine.medical_specialty
medicine.drug_class
Prostaglandin E2 receptor
Down-Regulation
Biology
Models
Biological
03 medical and health sciences
Trabecular Meshwork
Proto-Oncogene Proteins
Internal medicine
cAMP
PUMA
[SDV.BBM] Life Sciences [q-bio]/Biochemistry
Molecular Biology
medicine
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
Alprostadil
Protein kinase A
Molecular Biology
Intrinsic apoptosis
Cell Biology
Receptors
Prostaglandin E
EP2 Subtype
Cyclic AMP-Dependent Protein Kinases
030104 developmental biology
Endocrinology
Cytoprotection
Unfolded Protein Response
Unfolded protein response
Tumor Suppressor Protein p53
Apoptosis Regulatory Proteins
Transcription Factor CHOP
Zdroj: Biochimica et Biophysica Acta-Molecular Cell Research
Biochimica et Biophysica Acta-Molecular Cell Research, Elsevier, 2016, ⟨10.1016/j.bbamcr.2016.06.008⟩
Biochimica et Biophysica Acta-Molecular Cell Research, 2016, ⟨10.1016/j.bbamcr.2016.06.008⟩
ISSN: 0167-4889
DOI: 10.1016/j.bbamcr.2016.06.008⟩
Popis: International audience; E-prostanoid receptor subtype 2 (EP2) agonists are currently under clinical development as hypotensive agents for the treatment of ocular hypertension. However, the effects of EP2 receptor agonists on trabecular meshwork (TM) alterations leading to primary open-angle glaucoma (POAG) are still unknown. Here, we evaluated whether EP2 receptor activation exhibits protective functions on TM cell death induced by endoplasmic reticulum (ER) stress. We show that the EP2 receptor agonist butaprost protects TM cell death mediated by the ER stress inducer tunicamycin through a cyclic AMP (cAMP)-dependent mechanism, but independent of the classical cAMP sensors, protein kinase A and exchange proteins activated by cAMP. The ER stress-induced intrinsic apoptosis inhibited by the EP2 receptor agonist was correlated with a decreased accumulation of the cellular stress sensor p53. In addition, p53 down-regulation was associated with inhibition of its transcriptional activity, which led to decreased expression of the pro-apoptotic p53-upregulated modulator of apoptosis (PUMA). The stabilization of p53 by nutlin-3a abolished butaprost-mediated cell death protection. In conclusion, we showed that EP2 receptor activation protects against ER stress-dependent mitochondrial apoptosis through down-regulation of p53. The specific inhibition of this pathway could reduce TM alterations observed in POAG patients.
Databáze: OpenAIRE
Externí odkaz: