p53-independent apoptosis associated with c-Myc-mediated block in myeloid cell differentiation.
Previously we have shown that deregulated expression of c-myc in M1 myeloid leukemic cells blocked IL-6-induced differentiation and its associated growth arrest; however, the cells proliferated at a significantly reduced rate compared to untreated cells. The basis for the increased doubling time of IL-6-treated M1myc cells was found to be due to the induction of a p53-independent apoptotic pathway. The apoptotic response was not completely penetrant; in the same population of cells both proliferation and apoptosis were continuously ongoing. Down-regulation of Bcl-2 was insufficient to account for the apoptotic response, since deregulated expression of Bcl-2 delayed, but did not block, the onset of apoptosis. Furthermore, our results indicated that the IL-6-induced partial hypophosphorylation of the retinoblastoma gene product (Rb), observed in M1myc cells, was not responsible for the apoptotic response. Finally, the findings in M1 cells were extended to myeloid cells derived from the bone marrow of wild type and p53-deficient mice, where the deregulated expression of c-myc was also shown to block terminal differentiation and induce apoptosis independent of p53. These findings provide new insights into how myc participates in the neoplastic process, and how additional mutations can promote more aggressive tumors. Oncogene (2000) 19, 2967 - 2977
Amanullah
A
A
Fels Institute for Cancer Research and Molecular Biology, Department of Biochemistry, Temple University School of Medicine, 3307 N. Broad St., Philadelphia, Pennsylvania, PA 19140, USA.
Liebermann
D A
DA
Hoffman
B
B
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000502:physiology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000502:physiology*; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins
C493966:CDKN2B protein, human; D002352:Carrier Proteins; C493968:Cdkn2b protein, mouse; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015850:Interleukin-6; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins