Fos modulates myeloid cell survival and differentiation and partially abrogates the c-Myc block in terminal myeloid differentiation.
Previously, we have shown that Fos/Jun transcription factor complexes function as positive modulators of myeloid differentiation. Fos, which is stably induced during normal myeloid differentiation, is not induced upon differentiation of M1 myeloblastic leukemia cells. Establishing M1 cells that express a beta-estradiol-conditional FosER chimera, we show that in the absence of the differentiation inducer interleukin-6 (IL-6), Fos expression in M1 myeloblasts promoted apoptotic cell death, entailing cytochrome c release and caspase-9 activation. In contrast, in the presence of IL-6, Fos-mediated apoptosis was abrogated, and Fos promoted terminal differentiation, increasing the sensitivity of M1 cells to be induced for differentiation by IL-6. Fos-mediated apoptosis was accelerated by deregulated c-Myc. Furthermore, restoring Fos expression in M1 partially abrogated the block imparted by deregulated c-Myc on the myeloid differentiation program, increased the sensitivity of the cells to be induced for differentiation, and curtailed their leukemic phenotype. These data provide evidence that Fos/Jun transcription factor complexes play a role in modulating both myeloid cell survival and differentiation and suggest that genetic lesions that alter Fos expression may cooperate with deregulated c-Myc in leukemogenesis.
Fels Institute for Cancer Research and Molecular Biology, and Department of Biochemistry, Temple University School of Medicine, 3307 N Broad St, Philadelphia, PA 19140, USA.
Marianna
M
Shafarenko
Arshad
A
Amanullah
Bernard
B
Gregory
Dan A
DA
Liebermann
Barbara
B
Hoffman
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D045304:Cytochromes c / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D022423:Myeloid Cells / Q000166:cytology* / Q000378:metabolism*; D010641:Phenotype; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism
D015850:Interleukin-6; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D045304:Cytochromes c; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases