gms | German Medical Science

The p53 tumor suppressor is a central stress response protein, activated by multiple endogenous and environmental insults. UV-irradiation of cells activates p53, causes accumulation of the tumor suppressor in the nucleus and induces apoptosis. Recently it was shown that growth-arrested cells are resistant to UV-light induced p53-dependent apoptosis. In previous studies we could show that the human guanylate binding protein-1 (hGBP-1) mediates the inhibition of cell proliferation induced by IFN-γ and double-stranded (ds) RNA in endothelial cells (EC). Here we wanted to analyse the effect of hGBP-1 on nuclear translocation of p53 after UV-irradiation in human umbilical vein endothelial cells (HUVEC).

We found that an upregulation of hGBP-1 expression in HUVEC induced by IFN-γ and dsRNA was accompanied by a reduced p53 intracellular protein concentration. In addition pretreatment of HUVEC with IFN-γ and dsRNA inhibited the UV induced nuclear accumulation of p53. In untreated EC nuclear translocation of p53 following UV-irradiation (100J/m2) was not disturbed. In a next step hGBP-1 was constitutively expressed in HUVEC by retroviral-mediated gene transfer. Of note, in these cells UV induced nuclear translocation of p53 was significantly (p < 0,001; chi square test) repressed even without pretreatment with IFN-γ or dsRNA. After UV-irradiation only 36% of hGBP-1 transduced cells showed nuclear accumulation of p53 as compared to 72 % of vector transduced control cells.

These results suggest that hGBP-1 may mediate the inhibition of UV induced p53 nuclear translocation in response to IFN-γ and dsRNA. This activity may effect p53 dependent apoptosis and could be of relevance in anti-angiogenic tumor therapy.