TY - JOUR
T1 - p53-Dependent ICAM-1 overexpression in senescent human cells identified in atherosclerotic lesions
AU - Gorgoulis, Vassilis G.
AU - Pratsinis, Harris
AU - Zacharatos, Panayotis
AU - Demoliou, Catherine
AU - Sigala, Fragiska
AU - Asimacopoulos, Panayiotis J.
AU - Papavassiliou, Athanasios G.
AU - Kletsas, Dimitris
PY - 2005/4
Y1 - 2005/4
N2 - 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.
AB - 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.
KW - Aging
KW - Atherosclerosis
KW - Fibroblasts
KW - ICAM-1
KW - p53
KW - Smooth muscle cells
UR - http://www.scopus.com/inward/record.url?scp=17144400369&partnerID=8YFLogxK
U2 - 10.1038/labinvest.3700241
DO - 10.1038/labinvest.3700241
M3 - Article
C2 - 15711569
AN - SCOPUS:17144400369
SN - 0023-6837
VL - 85
SP - 502
EP - 511
JO - Laboratory Investigation
JF - Laboratory Investigation
IS - 4
ER -