SUPPRESSION OF BCL-2 MESSENGER-RNA PRODUCTION MAY MEDIATE APOPTOSIS AFTER IONIZING-RADIATION, TUMOR-NECROSIS-FACTOR-ALPHA, AND CERAMIDE

Recent studies have proposed that tumor necrosis factor alpha (TNF-alp ha) and ionizing radiation induce apoptosis by activating hydrolysis o f sphingomyelin to ceramide, Bcl-2 and a related gene, Bcl-X, inhibit several forms of apoptosis, Herein, we report that internucleosomal DN A fragmentation, characteristic of apoptosis and induced by ionizing r adiation, is accompanied by concomitant decreases in Bcl-2 and Bcl-X m RNA levels in HL-60 and U-937 human leukemia cells. Apoptotic DNA frag mentation after exposure to TNF-alpha and C-2-ceramide was also associ ated with down-regulation of Bcl-2 mRNA in HL-60 and U-937 cells, whil e Bcl-X mRNA production was unaffected, These results suggest that mod ulation of Bcl-2 gene expression may be a target for ceramide-mediated apoptosis following exposure to ionizing radiation and TNF-alpha. Cha nges in Bcl-2 expression may be the basis for the interactive killing observed between radiation and TNF-alpha in some human and tumor cells .