title: ATF6α regulates morphological changes associated with senescence in human fibroblasts.
abstract: Cellular senescence is known as an anti-tumor barrier and is characterized by a number of determinants including cell cycle arrest, senescence associated β-galactosidase activity and secretion of pro-inflammatory mediators. Senescent cells are also subjected to enlargement, cytoskeleton-mediated shape changes and organelle alterations. However, the underlying molecular mechanisms responsible for these last changes remain still uncharacterized. Herein, we have identified the Unfolded Protein Response (UPR) as a player controlling some morphological aspects of the senescent phenotype. We show that senescent fibroblasts exhibit ER expansion and mild UPR activation, but conserve an ER stress adaptive capacity similar to that of exponentially growing cells. By genetically invalidating the three UPR sensors in senescent fibroblasts, we demonstrated that ATF6α signaling dictates senescence-associated cell shape modifications. We also show that ER expansion and increased secretion of the pro-inflammatory mediator IL6 were partly reversed by silencing ATF6α in senescent cells. Moreover, ATF6α drives the increase of senescence associated-β-galactosidase activity. Collectively, these findings unveil a novel and central role for ATF6α in the establishment of morphological features of senescence in normal human primary fibroblasts.
authors: Université de Lille, Institut Pasteur de Lille, CNRS UMR8161, Mechanisms of Tumourigenesis and Targeted Therapies, Lille, France.|Department of Anatomy and Neuroscience, Biosciences Institute, University College Cork, Cork, Ireland.
authors: Clémentine
authors: C
authors: Druelle
authors: Université de Lille, Institut Pasteur de Lille, CNRS UMR8161, Mechanisms of Tumourigenesis and Targeted Therapies, Lille, France.
authors: Claire
authors: C
authors: Drullion
authors: Université de Lille, Institut Pasteur de Lille, CNRS UMR8161, Mechanisms of Tumourigenesis and Targeted Therapies, Lille, France.
authors: Julie
authors: J
authors: Deslé
authors: Université de Lille, Institut Pasteur de Lille, CNRS UMR8161, Mechanisms of Tumourigenesis and Targeted Therapies, Lille, France.
authors: Nathalie
authors: N
authors: Martin
authors: Université de Lille, Institut Pasteur de Lille, CNRS UMR8161, Mechanisms of Tumourigenesis and Targeted Therapies, Lille, France.
authors: Laure
authors: L
authors: Saas
authors: Université de Lille, Institut Pasteur de Lille, CNRS UMR8161, Mechanisms of Tumourigenesis and Targeted Therapies, Lille, France.
authors: Johanna
authors: J
authors: Cormenier
authors: Université de Lille, Institut Pasteur de Lille, CNRS UMR8161, Mechanisms of Tumourigenesis and Targeted Therapies, Lille, France.|Institut du Cancer de Montréal, Montréal, QC, Canada.
authors: Nicolas
authors: N
authors: Malaquin
authors: Université de Lille, Institut Pasteur de Lille, INSERM, CNRS UMR8204, Centre d'Infection et d'Immunité de Lille, Lille, France.
authors: Ludovic
authors: L
authors: Huot
authors: Université de Lille, INSERM U1003, Villeneuve d'Ascq, France.
authors: Christian
authors: C
authors: Slomianny
authors: Université de Lille, Institut Pasteur de Lille, CNRS UMR8161, Mechanisms of Tumourigenesis and Targeted Therapies, Lille, France.
authors: Fatima
authors: F
authors: Bouali
authors: Université de Lille, Institut Pasteur de Lille, CNRS UMR8161, Mechanisms of Tumourigenesis and Targeted Therapies, Lille, France.
authors: Chantal
authors: C
authors: Vercamer
authors: Université de Lille, Institut Pasteur de Lille, INSERM, CNRS UMR8204, Centre d'Infection et d'Immunité de Lille, Lille, France.
authors: David
authors: D
authors: Hot
authors: Université de Lille, Institut Pasteur de Lille, CNRS UMR8161, Mechanisms of Tumourigenesis and Targeted Therapies, Lille, France.
authors: Albin
authors: A
authors: Pourtier
authors: Oncogenesis, Stress, Signaling, INSERM ER-440 Université de Rennes, Rennes, France.|Centre de Lutte Contre le Cancer Eugene Marquis, Rennes, France.
authors: Eric
authors: E
authors: Chevet
authors: Université de Lille, Institut Pasteur de Lille, CNRS UMR8161, Mechanisms of Tumourigenesis and Targeted Therapies, Lille, France.
authors: Corinne
authors: C
authors: Abbadie
authors: Université de Lille, Institut Pasteur de Lille, CNRS UMR8161, Mechanisms of Tumourigenesis and Targeted Therapies, Lille, France.
authors: Olivier
authors: O
authors: Pluquet
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D002648:Child; D020405:Dermis / Q000166:cytology; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007223:Infant; D008297:Male; D046529:Microscopy, Electron, Transmission; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics; D056811:Unfolded Protein Response / Q000235:genetics*
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6
keywords: ATF6α; Gerotarget; endoplasmic reticulum; normal human dermal fibroblast; senescence; unfolded protein response