Most normal somatic cells enter a state called replicative senescence
after a certain number of divisions, characterized by irreversible
growth arrest. Moreover, they express a pronounced inflammatory
phenotype that could contribute to the aging process and the development
of age-related pathologies. Among the molecules involved in the
inflammatory response that are overexpressed in senescent cells and aged
tissues is intercellular adhesion molecule-1 (ICAM-1). Furthermore,
ICAM-1 is overexpressed in atherosclerosis, an age-related, chronic
inflammatory disease. We have recently reported that the transcriptional
activator p53 can trigger ICAM-1 expression in an nuclear factor-kappa B
(NF-kappa B)-independent manner (Gorgoulis et al, EMBO J. 2003; 22: 1567
- 1578). As p53 exhibits an increased transcriptional activity in
senescent cells, we investigated whether p53 activation is responsible
for the senescence-associated ICAM-1 overexpression. To this end, we
used two model systems of cellular senescence: ( a) human fibroblasts
and (b) conditionally immortalized human vascular smooth muscle cells.
Here, we present evidence from both cell systems to support a
p53-mediated ICAM-1 overexpression in senescent cells that is
independent of NF-kappa B. We also demonstrate in atherosclerotic
lesions the presence of cells coexpressing activated p53, ICAM-1, and
stained with the senescence-associated beta-galactosidase, a biomarker
of replicative senescence. Collectively, our data suggest a direct
functional link between p53 and ICAM-1 in senescence and age-related
disorders