title: Lamin B1 loss is a senescence-associated biomarker.
abstract: Cellular senescence is a potent tumor-suppressive mechanism that arrests cell proliferation and has been linked to aging. However, studies of senescence have been impeded by the lack of simple, exclusive biomarkers of the senescent state. Senescent cells develop characteristic morphological changes, which include enlarged and often irregular nuclei and chromatin reorganization. Because alterations to the nuclear lamina can affect both nuclear morphology and gene expression, we examined the nuclear lamina of senescent cells. We show here than lamin B1 is lost from primary human and murine cell strains when they are induced to senesce by DNA damage, replicative exhaustion, or oncogene expression. Lamin B1 loss did not depend on the p38 mitogen-activated protein kinase, nuclear factor-κB, ataxia telangiectasia-mutated kinase, or reactive oxygen species signaling pathways, which are positive regulators of senescent phenotypes. However, activation of either the p53 or pRB tumor suppressor pathway was sufficient to induce lamin B1 loss. Lamin B1 declined at the mRNA level via a decrease in mRNA stability rather than by the caspase-mediated degradation seen during apoptosis. Last, lamin B1 protein and mRNA declined in mouse tissue after senescence was induced by irradiation. Our findings suggest that lamin B1 loss can serve as biomarker of senescence both in culture and in vivo.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Freund
authors.forename: Remi-Martin
authors.initials: RM
authors.lastname: Laberge
authors.forename: Marco
authors.initials: M
authors.lastname: Demaria
authors.forename: Judith
authors.initials: J
authors.lastname: Campisi
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D015415:Biomarkers / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D016922:Cellular Senescence / Q000528:radiation effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism; D004307:Dose-Response Relationship, Radiation; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D034921:Lamin Type B / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015415:Biomarkers; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D034921:Lamin Type B; D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases