title: p19INK4d is involved in the cellular senescence mechanism contributing to heterochromatin formation.
abstract: BACKGROUND
  During evolution, organisms with renewable tissues have developed mechanisms to prevent tumorigenesis, including cellular senescence and apoptosis. Cellular senescence is characterized by a permanent cell cycle arrest triggered by both endogenous stress and exogenous stress. The p19INK4d, a member of the family of cyclin-dependent kinase inhibitors (INK4), plays an important role on cell cycle regulation and in the cellular DNA damage response. We hypothesize that p19INK4d is a potential factor involved in the onset and/or maintenance of the senescent state.
  
  
  METHODS
  Senescence was confirmed by measuring the cell cycle arrest and the senescence-associated β-galactosidase activity. Changes in p19INK4d expression and localization during senescence were determined by Western blot and immunofluorescence assays. Chromatin condensation was measured by microccocal nuclease digestion and histone salt extraction.
  
  
  RESULTS
  The data presented here show for the first time that p19INK4d expression is up-regulated by different types of senescence. Changes in senescence-associated hallmarks were driven by modulation of p19 expression indicating a direct link between p19INK4d induction and the establishment of cellular senescence. Following a senescence stimulus, p19INK4d translocates to the nucleus and tightly associates with chromatin. Moreover, reduced levels of p19INK4d impair senescence-related global genomic heterochromatinization. Analysis of p19INK4d mRNA and protein levels in tissues from differently aged mice revealed an up-regulation of p19INK4d that correlates with age.
  
  
  CONCLUSIONS
  We propose that p19INK4d participates in the cellular mechanisms that trigger senescence by contributing to chromatin compaction.
  
  
  CONCLUSIONS
  This study provides novel insights into the dynamics process of cellular senescence, a central tumor suppressive mechanism.
authors.affiliation: Laboratorio de Biología Molecular, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II, 1428 Ciudad de Buenos Aires, Argentina.
authors.forename: Silvina V
authors.initials: SV
authors.lastname: Sonzogni
authors.affiliation: Laboratorio de Biología Molecular, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II, 1428 Ciudad de Buenos Aires, Argentina.
authors.forename: María Florencia
authors.initials: MF
authors.lastname: Ogara
authors.affiliation: Laboratorio de Biología Molecular, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II, 1428 Ciudad de Buenos Aires, Argentina.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Belluscio
authors.affiliation: Laboratorio de Biología Molecular, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II, 1428 Ciudad de Buenos Aires, Argentina.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Castillo
authors.affiliation: Laboratorio de Biología Molecular, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II, 1428 Ciudad de Buenos Aires, Argentina.
authors.forename: María E
authors.initials: ME
authors.lastname: Scassa
authors.affiliation: Laboratorio de Biología Molecular, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón II, 1428 Ciudad de Buenos Aires, Argentina. Electronic address: ecanepa@qb.fcen.uba.ar.
authors.forename: Eduardo T
authors.initials: ET
authors.lastname: Cánepa
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D063646:Carcinogenesis; D059447:Cell Cycle Checkpoints / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D005786:Gene Expression Regulation; D006570:Heterochromatin / Q000235:genetics*; D051379:Mice; D001616:beta-Galactosidase / Q000096:biosynthesis
chemical_list: C493975:Cdkn2d protein, mouse; D050764:Cyclin-Dependent Kinase Inhibitor p19; D006570:Heterochromatin; D001616:beta-Galactosidase
keywords: Aging; CDK inhibitor; Cellular senescence; DNA damage; Heterochromatin