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-alpha) and ionizing radiation induce apoptosis by activating hydrolysis of sphingomyelin to ceramide. Bcl-2 and a related gene, Bcl-X, inhibit several forms of apoptosis. Herein, we report that internucleosomal DNA fragmentation, characteristic of apoptosis and induced by ionizing radiation, is accompanied by concomitant decreases in Bcl-2 and Bcl-X mRNA levels in HL-60 and U-937 human leukemia cells. Apoptotic DNA fragmentation after exposure to TNF-alpha and C2-ceramide was also associated with down-regulation of Bcl-2 mRNA in HL-60 and U-937 cells, while Bcl-X mRNA production was unaffected. These results suggest that modulation of Bcl-2 gene expression may be a target for ceramide-mediated apoptosis following exposure to ionizing radiation and TNF-alpha. Changes in Bcl-2 expression may be the basis for the interactive killing observed between radiation and TNF-alpha in some human and tumor cells.
Chen
M
M
Department of Radiation and Cellular Oncology, University of Chicago, Illinois 60637.
Quintans
J
J
Fuks
Z
Z
Thompson
C
C
Kufe
D W
DW
Weichselbaum
R R
RR
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects*; D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002518:Ceramides / Q000494:pharmacology*; D003131:Combined Modality Therapy; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects / Q000528:radiation effects; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D002518:Ceramides; D004273:DNA, Neoplasm; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein