D. Kletsas, H. Pratsinis, G. Mariatos, V.G. Gorgoulis

Senescent cells are characterized by an pro-inflammatory phenotype, possibly leading to detrimental effects on tissue homeostasis. Microarray analysis has shown that one of the genes found to be over-expressed in cellular senescence is ICAM-1 (Intracellular Adhesion Molecule-1) a crucial receptor in the cell-to-cell interaction, a process central to the reaction to all forms of injury. Its expression is up-regulated in response to a variety of inflammatory mediators, mostly via the NF-kB signalling pathway. On the other hand, p53 is strongly implicated in the activation of cellular senescence. Here we demonstrate that ICAM-1 induction represents one more cellular response to p53 activation, and in a NF-kB-independent manner. Induction of ICAM-1 is abolished after treatment with the specific p53 inhibitor pifithrin-a and abrogated in p53-deficient cell lines. Furthermore, we map three putative p53-responsive elements to the introns of the ICAM-1 gene. Chromatin immunoprecipitation assays indicated that two of these elements are functional, suggesting a direct induction of the ICAM-1 gene by p53. Concerning senescent cells, the over-expression of ICAM-1 is p53-dependent, as this phenomenon is annulled in the presence of pifithrin-a. The above support a direct p53-mediated ICAM-1 induction that may link p53 with various pathophysiologies, including cellular and organismal ageing

(Supported by the IPE 41/2001 project)

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