c-Myc induces apoptosis and cell cycle progression by separable, yet overlapping, pathways.
Enforced c-Myc expression promotes inappropriate cell cycle progression of growth factor deprived cells and triggers concomitant apoptosis. However, it is not clear what role dysregulation of the cell cycle plays in c-Myc-induced apoptosis. Ornithine decarboxylase (ODC) is a transcriptional target of c-Myc and contributes to c-Myc induced apoptosis. Here we have established that high levels of ODC overexpression in interleukin-3 (IL-3)-dependent 32D.3 myeloid cells induces apoptosis at rates comparable to those induced by enforced c-Myc expression. However, ODC-induced apoptosis was not accompanied by dysregulation of cell cycle controls, indicating that cell death was not triggered by inappropriate cell cycle progression. Nonetheless, ODC was required downstream of c-Myc for myeloid cell growth. These results suggested that c-Myc-induced pathways leading to cell cycle progression and apoptosis are separable, yet that they share common mediators. In agreement with this concept, treatment of cells over-expressing c-Myc with the growth inhibitory agent dibutyryl cyclic AMP (Bt2cAMP) arrested these cells G1, without inducing apoptosis. However, c-Myc retained the ability to induce apoptosis of Bt2cAMP-arrested cells following removal of IL-3, demonstrating that Bt2cAMP selectively inhibits c-Myc-induced pathways promoting cell cycle progression but not apoptosis. These results suggest a "multiple effectors' model in which c-Myc regulates the expression of mediators which alone are sufficient to induce apoptosis in the absence of survival factors, yet are required in concert to promote cell cycle progression.
Packham
G
G
Department of Biochemistry, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Porter
C W
CW
Cleveland
J L
JL
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D016259:Genes, myc; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D051379:Mice; D009955:Ornithine Decarboxylase / Q000096:biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000502:physiology*
D016271:Proto-Oncogene Proteins c-myc; D009955:Ornithine Decarboxylase