title: p21 both attenuates and drives senescence and aging in BubR1 progeroid mice.
abstract: BubR1 insufficiency occurs with natural aging and induces progeroid phenotypes in both mice and children with mosaic variegated aneuploidy syndrome. In response to BubR1 insufficiency, skeletal muscle, fat, and lens tissue engage p19(Arf) to attenuate senescence and age-related deterioration. Here, we address how p19(Arf) exerts this caretaker role using BubR1 progeroid mice lacking p53 or its transcriptional target p21. We show that p53 delays functional decline of skeletal muscle and fat in a p21-dependent fashion by inhibiting p16(Ink4a)-mediated senescence of progenitor cells. Strikingly, p53 also attenuates the formation of cataractous lenses, but here its antiaging effect is p21 independent, as we found p21 to promote senescence of lens epithelial cells and cataract formation. Together, these results demonstrate that p53 counteracts tissue destruction in response to BubR1 insufficiency through diverse mechanisms and uncover a causal link between senescence of the progenitor cell compartment and age-related dysfunction.
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Baker
authors.forename: Robbyn L
authors.initials: RL
authors.lastname: Weaver
authors.forename: Jan M
authors.initials: JM
authors.lastname: van Deursen
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000483:Alleles; D000818:Animals; D002386:Cataract / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D002460:Cell Line; D016922:Cellular Senescence; D025063:Chromosome Disorders / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D050764:Cyclin-Dependent Kinase Inhibitor p19 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D007908:Lens, Crystalline / Q000378:metabolism; D008136:Longevity; D051379:Mice; D009030:Mosaicism; D018482:Muscle, Skeletal / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; D050764:Cyclin-Dependent Kinase Inhibitor p19; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases