UP-REGULATION OF FAS (CD95) IN HUMAN P53(WILD-TYPE) CANCER-CELLS TREATED WITH IONIZING-RADIATION

Fas is a cell-surface protein which belongs to the tumor-necrosis-fact or-receptor family. Signals through Fas are able to induce apoptosis i n sensitive cells, and thus modalities for regulating the level of Fas expression on tumor cells are needed. We have studied cellular respon ses to gamma irradiation, The level of p53 tumor-suppressor protein wa s found to be elevated 3 hr after irradiation of p53(wild-type) MCF-7 breast-carcinoma cells. Interestingly, accumulation of p53 was followe d by up-regulation of surface Fas levels between 4 and 8 hr after irra diation, The level of Fas up-regulation was dependent on dose and, whe reas elevation in the level of p53 was transient, enhancement of Fas e xpression was stable. Fas up-regulation occurred coincidentally with i nduction of G(1) cell-cycle arrest, a post-irradiation phenomenon know n to be dependent on wild-type-p53 activity. We studied 9 other tumor lines, 2 with wild-type p53, 5 with mutant p53, and 2 expressing no p5 3, All lines expressing wild-type p53 were found to arrest in G(1) and to up-regulate Fas after irradiation. In contrast, all 7 p53(null) an d p53(mutant) lines failed not only to arrest their cell cycles in G(1 ) phase, but also to up-regulate Fas levels in response to treatment. These findings demonstrate a direct correlation between wild-type-p53 activity and Fas up-regulation after treatment with ionizing radiation , strongly suggesting that post-irradiation Fas up-regulation is depen dent on wild-type-p53 activity. Since low doses of radiation were suff icient to modulate Fas expression, up-regulation of the Fas death rece ptor may have clinical implications following radiotherapy. (C) 1997 W iley-Liss, Inc.