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Arsenite induces premature senescence via p53/p21 pathway as a result of DNA damage in human malignant glioblastoma cells

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In this study, we investigate whether arsenite-induced DNAdamage leads to p53-dependent premature senescence usinghuman glioblastoma cells with p53-wild type (U87MG-neo) andp53 deficient (U87MG-E6). A dose dependent relationship betweenarsenite and reduced cell growth is demonstrated, as wellas induced γH2AX foci formation in both U87MG-neo andU87MG-E6 cells at low concentrations of arsenite. Senescencewas induced by arsenite with senescence-associated β-galactosidasestaining. Dimethyl- and trimethyl-lysine 9 of histoneH3 (H3DMK9 and H3TMK9) foci formation was accompaniedby p21 accumulation only in U87MG-neo but not inU87MG-E6 cells. This suggests that arsenite induces prematuresenescence as a result of DNA damage with heterochromatinforming through a p53/p21 dependent pathway. p21 and p53siRNA consistently decreased H3TMK9 foci formation in U87MG-neo but not in U87MG-E6 cells after arsenite treatment. Taken together, arsenite reduces cell growth independently ofp53 and induces premature senescence via p53/p21-dependentpathway following DNA damage.

Abstract

In this study, we investigate whether arsenite-induced DNAdamage leads to p53-dependent premature senescence usinghuman glioblastoma cells with p53-wild type (U87MG-neo) andp53 deficient (U87MG-E6). A dose dependent relationship betweenarsenite and reduced cell growth is demonstrated, as wellas induced γH2AX foci formation in both U87MG-neo andU87MG-E6 cells at low concentrations of arsenite. Senescencewas induced by arsenite with senescence-associated β-galactosidasestaining. Dimethyl- and trimethyl-lysine 9 of histoneH3 (H3DMK9 and H3TMK9) foci formation was accompaniedby p21 accumulation only in U87MG-neo but not inU87MG-E6 cells. This suggests that arsenite induces prematuresenescence as a result of DNA damage with heterochromatinforming through a p53/p21 dependent pathway. p21 and p53siRNA consistently decreased H3TMK9 foci formation in U87MG-neo but not in U87MG-E6 cells after arsenite treatment. Taken together, arsenite reduces cell growth independently ofp53 and induces premature senescence via p53/p21-dependentpathway following DNA damage.

참고문헌 (40)

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