• Cells cannot proliferate indefinitely - they do not divide despite nutrients, growth
factors and space
• These cells are neither mitotic or post-mitotic cell and are different from prolifer-
ative and differentiated cells
•Altered morphology in culture
•Growth-arrest (typically in G0 due to high levels of cell-cycle inhibitors)
•Resistance to apoptosis (resistant to loss of growth factors, susceptible to
•Altered gene expression (increase the expression of p16 and p21, de-
creased expression of c-fos and cyclins)
•Causes of cellular senescence
• Telomere-dependent senescence - stretches of repetitive DNA and associated
proteins that cap the ends of linear chromosomes and protect them from
degradation or fusion by DNA-repair processes. Cell lose 50-200 base pairs of
telomeric DNA during each S-phase. The end-replication problem will eventu-
ally render the telomeres too short and critically non-functional. This causes
cells to not proliferation indefinitely because the lack of telomeres will cause
DNA damage and the cell will senesce.
• DNA damage will also cause senescence. This depends on p53, p16 and p21.
• Senescence caused by chromatin perturbation - chromatin state determines
the extent to which genes are active (euchromatin) or silent (heterochro-
matin). Histone deacetylase inhibition (HDAi) is thought to induce senes-
cence. One possibility is through the upregulation of p21 and p16.
• Oncogene-induced senescence - normal cells respond to many oncogenes by
• Stress and other inducers of senescence - oxidative damage and inappropri-
ate extracellular conditions cause senescence
•Senescence growth arrest is established and maintained by p53 and p16-pRb tu-
mour suppressor pathways.
•p53 is constantly synthesized and is usually titrated away by Mdm2 w