Regulation of bcl-2, bcl-XL and bax in the control of apoptosis by hematopoietic cytokines and dexamethasone.
Treatment of M1 myeloid leukemic cells with interleukin 6 (IL-6) or dexamethasone (DEX), both of which induce differentiation in these cells, down-regulated expression of the apoptosis-suppressing gene bcl-2 and the apoptosis-promoting gene bax but up-regulated expression of the apoptosis-suppressing gene bcl-XL. There was a higher expression of bcl-XL in cells treated with DEX or DEX plus IL-6 compared to cells treated with IL-6 alone. The alternatively spliced bcl-X gene, bcl-Xs, which interferes with the action of bcl-2, was not expressed. Treatment with IL-6 increased the susceptibility of these cells to induction of apoptosis by Adriamycin or cycloheximide, but treatment with DEX or with IL-6 and DEX did not. Withdrawal of DEX after up-regulation of bcl-XL resulted in a decrease in bcl-XL expression and a concomitant increase in cell susceptibility to induction of apoptosis. Another myeloid leukemia that shows barely detectable expression of bcl-2 also showed up-regulated expression of bcl-XL but no change in bax after induction of differentiation with granulocyte-macrophage colony-stimulating factor, and this reduced cell susceptibility to induction of apoptosis by Adriamycin or cycloheximide. The results indicate that the related apoptosis-regulating genes bcl-2, bcl-XL, and bax are differently regulated and that up-regulation of bcl-XL expression may compensate for down-regulation of bcl-2 in the balance between genes that control apoptosis.
Lotem
J
J
Department of Molecular Genetics and Virology, Weizmann Institute of Science, Rehovot, Israel.
Sachs
L
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D003520:Cyclophosphamide / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000473:pathology*; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D012326:RNA Splicing; D012334:RNA, Neoplasm / Q000235:genetics; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D015850:Interleukin-6; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012334:RNA, Neoplasm; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D003907:Dexamethasone; D004317:Doxorubicin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide