Chronic inflammation and neoplastic transformation are associated since it is well known that an increased cancer risk exists in chronically inflamed tissues. Cells, continuously encountering DNA damage and failuring to properly DNA repair, can lead to various disorders, including enhanced rates of tumor development. DNA damage checkpoint molecules (ATR, Chk1, H2AX) inhibit the cycline-dependent kinase machinery, which is known to coordinate DNA replication and chromosome partition (1). We previously demonstrated that the inflammatory mediator prostaglandin F2alpha (PGF2alpha) up-regulated multiple proliferative and survival signals on osteoblasts (2) and enhanced nuclear accumulation and co-localization of Bcl2 and c-Myc oncoproteins (3). Since the nuclear localization of Bcl2 is associated with mutagenesis and genome instability, the goal of this study was to examine whether PGF2alpha could participate on DNA damage. Indeed, primary calvarial osteoblasts showed a statistically significant increase of base lesion/cell after 24 h of PGF2alpha treatment. In addition, western blotting data evidenced that PGF2alpha increased phospho-ATR which, in turn, activated Chk1 kinase. Interestingly, immunofluorescence and western blotting data also demonstrated an increased level of phospho-H2AX which is known to be activated in the chromatin microenvironment surrounding a DNA double-strand break. On this regard, it is also important to note that PGF2alpha induced upregulation of the above check-point molecules and, in parallel, stimulated cell cycle progression. Further studies are in progress to better clarify the biological relevance of these findings.

PGF2alpha activates DNA damage check-point molecules on osteoblasts

AGAS, DIMITRIOS;SABBIETI, Maria Giovanna;MARCHETTI, Luigi
2011-01-01

Abstract

Chronic inflammation and neoplastic transformation are associated since it is well known that an increased cancer risk exists in chronically inflamed tissues. Cells, continuously encountering DNA damage and failuring to properly DNA repair, can lead to various disorders, including enhanced rates of tumor development. DNA damage checkpoint molecules (ATR, Chk1, H2AX) inhibit the cycline-dependent kinase machinery, which is known to coordinate DNA replication and chromosome partition (1). We previously demonstrated that the inflammatory mediator prostaglandin F2alpha (PGF2alpha) up-regulated multiple proliferative and survival signals on osteoblasts (2) and enhanced nuclear accumulation and co-localization of Bcl2 and c-Myc oncoproteins (3). Since the nuclear localization of Bcl2 is associated with mutagenesis and genome instability, the goal of this study was to examine whether PGF2alpha could participate on DNA damage. Indeed, primary calvarial osteoblasts showed a statistically significant increase of base lesion/cell after 24 h of PGF2alpha treatment. In addition, western blotting data evidenced that PGF2alpha increased phospho-ATR which, in turn, activated Chk1 kinase. Interestingly, immunofluorescence and western blotting data also demonstrated an increased level of phospho-H2AX which is known to be activated in the chromatin microenvironment surrounding a DNA double-strand break. On this regard, it is also important to note that PGF2alpha induced upregulation of the above check-point molecules and, in parallel, stimulated cell cycle progression. Further studies are in progress to better clarify the biological relevance of these findings.
2011
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/242111
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