Abstract A20: Excess centrosomes induce p53-dependent senescence in endothelial cells

Excess centrosomes (>2 centrosomes/cell), which are prevalent in both tumor cells and tumor endothelial cells, lead to aneuploidy and chromosome instability. Therefore, understanding how excess centrosomes affect cell behaviors is critical for studying tumor progression and tumor angiogenesis. As demonstrated by previous literature, cells with excess centrosomes routinely undergo bipolar cell division to produce viable progeny. However, we found that endothelial cells were not able to maintain the percentage of cells with excess centrosomes, suggesting that excess centrosomes had a negative impact on endothelial cell cycle. We used a tetracycline-inducible Polo-like kinase 4 (Plk4)-expressing system to induce excess centrosomes in human umbilical vein endothelial cells (HUVEC). Doxycycline treatment induced ~30% centrosome over-duplication, which decreased to <5% in 6 days. We found that HUVEC with excess centrosomes activated p53 by phosphorylating p53 at Ser33. Complete down-regulation of p53 helped maintain the frequency of cells with excess centrosomes. Excess centrosomes-induced p53 activation was independent of DNA damage, as demonstrated by lack of p53 Ser15 phosphorylation or H2AX foci. Excess centrosomes induced senescence but not apoptosis, as shown by senescence-associated beta-galactosidase (SA-β-gal) activity and Galactosidase Beta 1 (GLB1) antibody staining, and the induced senescence can be blocked by p53 down-regulation. Since endothelial cells main...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Getting out of Cycle: G0 and Senescence: Poster Presentations - Proffered Abstracts Source Type: research