title: ER Stress Response in Human Cellular Models of Senescence.
abstract: The aging process is characterized by progressive accumulation of damaged biomolecules in the endoplasmic reticulum, as result of increased oxidative stress accompanying cellular senescence. In agreement, we hypothesized that WI-38 human cellular models of replicative senescence and stress-induced premature senescence (SIPS) induced by hydrogen peroxide (H2O2-SIPS) or copper sulfate (CuSO4-SIPS) would present endoplasmic reticulum chaperoning mechanisms impairment and unfolded protein response activation. Results show that in replicative senescence and CuSO4-SIPS, immunoglobulin binding protein, calnexin, protein disulfide isomerase, and ER oxireductin-1 levels adjust to restore proteostasis and inositol-requiring enzyme-1 (IRE1)-, activating transcription factor 6 (ATF6)-, and pancreatic ER kinase (PERK)-mediated unfolded protein response are activated. However, H2O2-SIPS does not exhibit IRE1 and ATF6 pathways activation but a PERK-mediated upregulation of CCAAT/enhancer-binding protein homologous protein, showing that CuSO4-SIPS mimics better the endoplasmic reticulum molecular events of replicative senescence than H2O2-SIPS. Moreover, unfolded protein response activation is required for both SIPS models induction, because PERK and IRE1 inhibitors decreased senescence-associated beta-galactosidase appearance. In CuSO4-SIPS, the decrease in senescence levels is associated with PERK-driven, but IRE1 independent, cell cycle arrest while in H2O2-SIPS cell proliferation is PERK independent. These results add a step further on the molecular mechanisms that regulate senescence induction; moreover, they validate CuSO4-SIPS model as a useful tool to study cellular stress responses during aging, hoping to postpone age-related health decline.
authors.affiliation: Faculdade de Medicina do Porto, Departamento de Biologia Experimental, IBMC-Instituto de Biologia Molecular e Celular, Ageing and Stress, Universidade do Porto, Porto, Portugal. Faculdade de Ciências da Nutrição e Alimentação, Universidade do Porto, Porto, Portugal.
authors.forename: Liliana
authors.initials: L
authors.lastname: Matos
authors.affiliation: Faculdade de Medicina do Porto, Departamento de Biologia Experimental, IBMC-Instituto de Biologia Molecular e Celular, Ageing and Stress, Universidade do Porto, Porto, Portugal. Faculdade de Ciências da Nutrição e Alimentação, Universidade do Porto, Porto, Portugal.
authors.forename: Alexandra Monteiro
authors.initials: AM
authors.lastname: Gouveia
authors.affiliation: Faculdade de Medicina do Porto, Departamento de Biologia Experimental, IBMC-Instituto de Biologia Molecular e Celular, Ageing and Stress, Universidade do Porto, Porto, Portugal. almeidah@med.up.pt.
authors.forename: Henrique
authors.initials: H
authors.lastname: Almeida
mesh_terms: D051702:Activating Transcription Factor 6 / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D016922:Cellular Senescence; D004268:DNA-Binding Proteins / Q000235:genetics; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000502:physiology; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics; D019892:eIF-2 Kinase / Q000502:physiology
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C460640:EIF2AK3 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases
keywords: Copper; ER stress; Human fibroblasts; Replicative senescence; SIPS