p53-dependent ICAM-1 overexpression in senescent human cells identified in atherosclerotic lesions.
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-kappaB)-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-kappaB. 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.
Gorgoulis
Vassilis G
VG
Department of Histology and Embryology, Medical School, University of Athens, Athens, Greece.
Pratsinis
Harris
H
Zacharatos
Panayotis
P
Demoliou
Catherine
C
Sigala
Fragiska
F
Asimacopoulos
Panayiotis J
PJ
Papavassiliou
Athanasios G
AG
Kletsas
Dimitris
D
D001161:Arteriosclerosis / Q000378:metabolism*; D001483:Base Sequence; D016922:Cellular Senescence; D017931:DNA Primers; D006801:Humans; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D017931:DNA Primers; D016328:NF-kappa B; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D018799:Intercellular Adhesion Molecule-1