Many proto-oncogenes participate in the regulation of apoptosis. Closely intertwined with actions of oncogenes are various growth factors and other genes that participate in the control of cellular growth. c-Myc plays a critical role in multiple cellular processes including cell growth, proliferation, differentiation and apoptosis. C-Myc activity is sufficient to drive cells into the cell cycle in the absence of growth factors but also induces apoptosis when survival factors are missing. The quantity of c-Myc is carefully controlled by many mechanisms and it exerts its oncogenic effects through regulation of genes involved in growth and proliferation.
Expression of c-Myc sensitizes cells to a wide range of mechanistically diverse pro-apoptotic processes including DNA damage, death receptor signaling, hypoxia, genotoxic stress, and nutrient deprivation. Two discrete pro-apoptotic effector pathways mediate this sensitization. One of these involves stabilization of p53 through the ARF/MDM2 pathway, which serves as a sentinel for genotoxic damage. The second promotes release of Cytochrome C (CytoC) from mitochondria into the cytosol through activation of the pro-apoptotic molecule BAX, by a mechanism that is independent of both the Fas-FasL and the DNA damage pro-apoptotic pathways. Activated BAX within the mitochondrial membrane leads to creation or alteration of membrane pores, resulting in mitochondrial outer membrane permeabilization (MOMP). Once released into the cytosol, CytoC associates with APAF1 and procaspase 9 to form the apoptosome. In the presence of ATP, caspase 9 is activated leading to activation of downstream effector caspases including caspase 3, which ultimately leads to the degradation of cell components and the demise of the cell. Since the release of cytoC is the principal target for suppression by survival factors, this pathway acts as a trophic sentinel, triggering C-Myc-induced apoptosis. C-Myc-induced release of CytoC is also suppressed by BCL2/BCL-XL, which, like survival factors, potently exacerbate c-Myc oncogenicity. Both of these apoptotic pathways share APAF1 and caspase 9 as final apoptotic effectors downstream of the mitochondrion. Inhibition of this mitochondrial pathway, either by suppression of cytoC release by pro-survival proteins BCL2/BCL-XL, or by incapacity of the downstream mitochondrial apoptotic effector pathway through genetic loss of APAF1 or caspase 9, inhibits c-Myc-induced apoptosis and promotes c-Myc oncogenicity.
Ectopic expression of the death receptor signaling proteins or ligation of the death receptor Fas triggers the association of the intracellular adaptor protein FADD, which then recruits pro-caspase 8, resulting in its auto-activation. Caspase 8 also activates the pro-apoptotic protein BID by cleavage, which promotes MOMP. Survival signals that serve to block c-Myc-induced apoptosis include signaling via the IGF1R or activated Ras, which leads to the activation of AKT and subsequent phosphorylation of the pro-apoptotic protein BAD. Phosphorylated BAD is sequestered and inactivated by cytosolic 14-3-3 proteins. Anti-apoptotic proteins BCL2 and BCL-XL also block cytoC release, possibly through the sequestration of BAX.
C-Myc activates the cell cycle machinery and intriguingly, its ability to activate glycolysis suggests that in addition to triggering the cell cycle, c-Myc also sustains the necessary threshold to run the cell cycle machinery. Indeed, its ability to enhance the activities of specific enzymes involved in DNA metabolism and other metabolic pathways further suggests that it is a key molecular integrator of cell cycle machinery and cellular metabolism.