title: Ciliary abnormalities in senescent human fibroblasts impair proliferative capacity.
abstract: Somatic cells senesce in culture after a finite number of divisions indefinitely arresting their proliferation. DNA damage and senescence increase the cellular number of centrosomes, the 2 microtubule organizing centers that ensure bipolar mitotic spindles. Centrosomes also provide the basal body from which primary cilia extend to sense and transduce various extracellular signals, notably Hedgehog. Primary cilium formation is facilitated by cellular quiescence a temporary cell cycle exit, but the impact of senescence on cilia is unknown. We found that senescent human fibroblasts have increased frequency and length of primary cilia. Levels of the negative ciliary regulator CP110 were reduced in senescent cells, as were levels of key elements of the Hedgehog pathway. Hedgehog inhibition reduced proliferation in young cells with increased cilium length accompanying cell cycle arrest suggesting a regulatory function for Hedgehog in primary ciliation. Depletion of CP110 in young cell populations increased ciliation frequencies and reduced cell proliferation. These data suggest that primary cilia are potentially novel determinants of the reduced cellular proliferation that initiates senescence.
authors.affiliation: a Center for Chromosome Biology; School of Natural Sciences ; National University of Ireland Galway ; Galway , Ireland.
authors.forename: Loretta
authors.initials: L
authors.lastname: Breslin
authors.forename: Suzanna L
authors.initials: SL
authors.lastname: Prosser
authors.forename: Sandra
authors.initials: S
authors.lastname: Cuffe
authors.forename: Ciaran G
authors.initials: CG
authors.lastname: Morrison
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence; D002923:Cilia / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism
chemical_list: C467559:CCP110 protein, human; D018797:Cell Cycle Proteins; D053823:Hedgehog Proteins; D008869:Microtubule-Associated Proteins; D010750:Phosphoproteins
keywords: CP110; CP110, centriolar coiled coil protein of 110kDa; DABCO, 1,4-Diazabicyclo[2.2.2]octane; DAPI, 4′,6-diamidino-2-phenylindole; ECL, enhanced chemiluminescence; FITC, Fluorescein isothiocyanate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HMEC, human mammary epithelial cell; Hedgehog; Hh, Hedgehog; NHDF, normal human dermal fibroblasts; PLK4, Polo-like kinase 4; SA-β-gal, senescence-associated β-galactosidase; SAHF, senescence-associated heterochromatin foci; Smo, smoothened; centrosome; primary cilium; replicative senescence