p53-Dependent ICAM-1 overexpression in senescent human cells identified in atherosclerotic lesions

Vassilis G. Gorgoulis, Harris Pratsinis, Panayotis Zacharatos, Catherine Demoliou, Fragiska Sigala, Panayiotis J. Asimacopoulos, Athanasios G. Papavassiliou, Dimitris Kletsas

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Abstract

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-κB)-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-κB. We also demonstrate in atherosclerotic lesions the presence of cells coexpressing activated p53, ICAM-1, and stained with the senescence-associated β-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.

Original languageEnglish
Pages (from-to)502-511
Number of pages10
JournalLaboratory Investigation
Volume85
Issue number4
DOIs
Publication statusPublished - Apr 2005

Keywords

  • Aging
  • Atherosclerosis
  • Fibroblasts
  • ICAM-1
  • p53
  • Smooth muscle cells

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    Gorgoulis, V. G., Pratsinis, H., Zacharatos, P., Demoliou, C., Sigala, F., Asimacopoulos, P. J., Papavassiliou, A. G., & Kletsas, D. (2005). p53-Dependent ICAM-1 overexpression in senescent human cells identified in atherosclerotic lesions. Laboratory Investigation, 85(4), 502-511. https://doi.org/10.1038/labinvest.3700241