Suppression of c-myc and c-myb is tightly linked to terminal differentiation induced by IL6 or LIF and not growth inhibition in myeloid leukemia cells.
Cell proliferation and differentiation are intimately related processes where the proto-oncogenes c-myc and c-myb have been implicated to play a role. Previously, we have shown that both c-myc and c-myb were induced in normal myeloid precursors when the cells were stimulated for growth, were expressed in the autonomously proliferating myeloid leukemic M1 cell line and were rapidly suppressed in both normal and M1 cells following induction of terminal differentiation associated with growth arrest. In order to distinguish molecular events associated with terminal differentiation versus those due to growth inhibition, as well as to increase our understanding of the role of the proto-oncogenes c-myc and c-myb in both of these cellular processes, in this work we have studied the expression of c-myc and c-myb in M1 cells induced for growth inhibition associated with terminal differentiation (via treatment with the physiological inducers IL6 or leukemia inhibitory factor mean value of LIF), partial differentiation (using IL1 or LPS) or no detectable differentiation properties (using IFN beta or IFN gamma). We show that, for all the treatments used in this study, down regulation of the proto-oncogenes c-myc and c-myb occurred only when M1 cells were stimulated to undergo terminal differentiation. In addition, we transfected the M1 cell line with a vector containing the c-myc gene under control of the beta-actin promoter, so that c-myc was no longer down regulated by IL6 or LIF. Previously, we have shown that in the presence of the myeloid differentiation inducers IL6 or LIF, these M1myc cells were blocked at an intermediate stage of myeloid differentiation and continued to proliferate. In sharp contrast to their altered response to IL6 or LIF, M1myc cells were as responsive as the parental M1 cells to growth suppression by the different antiproliferative compounds which do not induce terminal differentiation. Thus, continued expression of c-myc had no effect on growth suppression induced by IL1, IFN beta, IFN gamma and LPS. Taken together, these results indicate that c-myc and c-myb down regulation is not necessary for growth suppression, but down regulation of c-myc is, and c-myb may be, essential for terminal differentiation.
Hoffman-Liebermann
B
B
Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia 19104.
Liebermann
D A
DA
D000818:Animals; D015152:Blotting, Northern; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000502:physiology; D006131:Growth Inhibitors; D007370:Interferon Type I / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology*; D053605:Leukemia Inhibitory Factor; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008222:Lymphokines / Q000494:pharmacology*; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D013489:Suppression, Genetic / Q000235:genetics* / Q000502:physiology
D006131:Growth Inhibitors; D007370:Interferon Type I; D007375:Interleukin-1; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008070:Lipopolysaccharides; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D016271:Proto-Oncogene Proteins c-myc; D007371:Interferon-gamma