The primary cilium as a regulator of cellular senescence in human fibroblasts
MetadataShow full item record
This item's downloads: 444 (view details)
Somatic cells senesce in culture after a finite number of divisions, indefinitely arresting their proliferation. Among the major causes of senescence is persistent DNA damage signalling. DNA damage and senescence increase the cellular number of centrosomes, the two microtubule organising centres that ensure bipolar mitotic spindles. Centrosomes also provide the basal body, a foundation for the formation of primary cilia, microtubule-based organelles that extend from the surface of most human cell types to sense and transduce various extracellular signals. Primary cilium formation is facilitated by cellular quiescence, a temporary exit from the cell cycle, but the impact of senescence on cilia has not been described. In this project we show that increased cilium frequency and length accompanies senescence in primary human fibroblasts and that ciliation induced by depletion of the centriolar protein CP110 causes senescence. A higher frequency of senescent BJ, MRC5 and NHDF cells had a primary cilium compared to proliferating controls. Cilia were significantly longer on senescent cells. Senescent BJ fibroblasts have elevated numbers of centrioles and this correlates with an increase in ciliary abnormality. Senescent cells showed reduced expression levels of components of the Hedgehog signalling pathway. Inhibition of Hedgehog signalling with cyclopamine reduced proliferation in young cell populations, with increased cilium length accompanying the induction of cell cycle arrest. Ciliary regrowth experiments demonstrated that cilium length is independent of the growth arrest period and that it is intrinsic to the cell. Senescent cells showed reduced levels of the negative ciliary length regulator, CP110. siRNA-mediated depletion of CP110 in young populations increased ciliation, reduced proliferation and elevated cellular senescence. These data demonstrate that primary cilium length regulation through CP110 is a potential novel determinant of cellular proliferative capacity.
This item is available under the Attribution-NonCommercial-NoDerivs 3.0 Ireland. No item may be reproduced for commercial purposes. Please refer to the publisher's URL where this is made available, or to notes contained in the item itself. Other terms may apply.
The following license files are associated with this item: