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Senescence
Hayflick first described
cellular senescence in the 1960s as a cell cycle
arrest that accompanies the exhaustion of the replicative potential
of human diploid fibroblasts in culture. Senescence cells continue
to be metabolically active and develop a large, flat morphology,
display characteristic changes in gene expression, typically
exhibit a senescence-associated ß-galactosidase (SA-ß-gal)
activity and accumulate a distinct heterochromatin structure,
termed senescence-associated heterochromatin foci (SAHFs). Senescence
is a highly irreversible form of growth arrest and once it is
established, cells are unable to express genes required for
proliferation, even in a strong pro-mitogenic environment. These
features distinguish senescence from quiescence, a non-proliferative
state that is readily reversed in response to mitogens.
In addition to replicative
exhaustion, a plethora of other insults such
as mild oxidative stress, atmospheric oxygen, tissue culture
on plastic, treatment with chemotherapeutic drugs or oncogene
expression trigger a response indistinguishable from replicative
senescence. Especially interesting is oncogene-induced senescence
(OIS) as it provides a link between senescence and cancer. There
is an abundance of experimental evidence, including recent results
from our group, that OIS is a tumour suppressor mechanism hindering
cancer progression in vivo.
At the molecular level, replicative
senescence of human cells i triggered by telomere
attrition, which is registered by the cell as DNA damage and
results eventually in the activation of p53. During replicative
senescence the CDK inhibitor p16INK4a accumulates
in the cell, inhibiting the CDK-mediated phosphorylation of
Rb, therefore contributing to a G1 cell cycle arrest. Although
subtle differences exist depending on the stimuli and the cell
type in which senescence is studied, we can tell that these
two pathways (the p53 and the p16INK4a/Rb pathways)
are central to senescence control. The interest of our group
in studying senescence is due to its intimate relation with
cancer and the fact that genes regulating senescence are almost
invariably linked with oncogenesis.
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Cellular senescence.
Left, typical brightfield image comparing proliferating
(top) and senescent (bottom, showing flat and enlarged
morphology) mouse embryonic fibroblasts. Right, schema
of the pathways involved in senescence and the entry points
where various stimuli engage them. |
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