Effect of NP95 Deficiency on Caffeine Action in Mouse Embryonic Stem Cells

Abstract

Radiosensitization together with abrogated cell cycle checkpoints are most pronounced actions of caffeine among its many diversified activities. Caffeine has recently been considered to overcome the G2/M and S checkpoint responses through its inhibition of phosphorylation of ATM /ATR kinase substrates including Chlk1, Chk2 and P53. We have found that homozygouly Np95-inactivated embryonic stem (ES) cells are more sensitive to X-rays, UV-light, MNNG, and HU than ES wild type cells, mimicking the phenotype of ATRkd human fibroblasts or Chk1-/- cells. To explore the relationship between ATR and NP95 we examined the effect of Np95 status on the caffeine action in ES cells. Two mM caffeine in the post irradiation medium enhanced the cytotoxicity of UVC in Np95 +/+ cells, but not in Np95 -/- cells, while synergism was more pronounced in Np95 -/- cells than Np95 +/+ cells following the treatment with X-rays. [J Radiat Res 44:409 (2003)]