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 overexpressing c-Myc with the inhibitory agent dibutyryl cyclic AMP (Bt(2)cAMP) arrested these cells G(1), without inducing apoptosis. However, c-Myc retained the ability to induce apoptosis of Bt(2)cAMP-arrested cells following removal of IL-3, demonstrating that Bt(2)cAMP selectively inhibits c-Myc-induced pathways promoting cell cycle progression but not apoptosis. These results suggest a 'multiple effecters' 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.