Phosphatidylinositol 3-kinase/Akt signaling mediates interleukin-6 protection against p53-induced apoptosis in M1 myeloid leukemic cells.
M1 myeloid leukemic cells were used to dissect the molecular mechanisms of myeloid cell survival and apoptosis. A salient feature of M1 cells is that they respond to the physiological survival factor interleukin-6 (IL-6), yet lack the tumor suppressor gene p53. Functional wild-type activation of temperature-sensitive p53 protein (p53 val) at permissive temperature in M1-t-p53 cells results in rapid apoptosis, which is blocked by IL-6. How p53 induces M1 apoptosis and how IL-6 protects against p53-induced apoptosis are not fully understood. Here it is shown that p53-mediated apoptosis of M1 cells involves rapid activation of the proapoptotic Fas/CD95 death pathway, which activates caspases 8 and 10. Functional p53 also targets the mitochondria, causing upregulation of proapoptotic Bax, downregulation of prosurvival Bcl-2 and activation of caspase 9. IL-6 was found to protect against p53-induced apoptosis via activation of the PI3K/Akt survival pathway, which in turn counters both the Fas/CD95 and mitochondrial apoptotic pathways and activates the prosurvival transcription factor nuclear factor-kappaB (NF-kappaB). Taken together, this work supports a novel model for leukemic progression where cells that acquire the ability to produce an autocrine survival factor, such as IL-6, can bypass normal p53 surveillance function by targeting Akt, which in turn can exert effects on the regulators of apoptosis, such as the Fas/CD95 pathway, the mitochondria and NF-kappaB.
Vesely
D L
DL
Fels Institute for Cancer Research & Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Hoffman
B
B
Liebermann
D A
DA
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology*; D007951:Leukemia, Myeloid / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D015850:Interleukin-6; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt