Figure 1.

Apoptotic signaling pathways in normal and malignant cells. Fundamental differences in MYC-linked signaling pathways distinguish normal and malignant cells. (Left) In normal cells whose environment has adequate nutrients and growth factors, surveillance mechanisms such as p53 activation are not triggered. This is due in part to lack of flux through stress signaling pathways and in part to negative autoregulation that allows elevated MYC levels to trigger a block in further MYC expression. Unbridled MYC expression can activate the oncogene-stress pathway that signals via the p14ARF/MDM2 pathway to stimulate p53-mediated apoptosis. However, MYC levels in normal cells typically do not reach levels high enough to activate the p14ARF tumor suppressor. (Center) When growth factors are limiting, cells with high MYC levels experience activation of surveillance mechanisms, such as p53 induction. These changes ultimately culminate in apoptosis, as a means of eliminating incipient tumor cells from the organism. (Right) Tumor cells have constitutively elevated MYC, generally as the result of chromosomal translocation, MYC gene amplification, or tonic WNT signaling. By loss of surveillance mechanisms (e.g., p14ARF or p53 mutation, MDM2 overexpression) and/or by gain of prosurvival signals (e.g., BCL-2 and NF-κB pathway alterations), tumor cells are able to tolerate constitutively elevated MYC and avoid apoptosis. At least conceptually, the restoration of MYC-driven apoptosis signaling pathways in tumor cells yields promise as an anticancer therapy.