Figure 2

The ARF-p53 circuit in tumour development and therapy. Activation of Myc and Ras can force proliferation or trigger apoptosis. These oncogenic signals engage the tumor-suppressor network at many points, including through the ARF-p53 circuit shown here. Which components contribute most to tumor suppression depends on context. For example, Myc activates p53 to promote apoptosis while interfering with its ability to induce growth arrest by p21. Conversely, Ras activates p53 to promote growth arrest while suppressing apoptosis. This simplified view helps explain why, despite the potential of p53 to control several processes; apoptosis is primarily responsible for p53-mediated tumor suppression. DNA damage and oncogene signaling engage the tumor-suppressor network at different points and, as such, DNA-damage signaling relies more on p53 than on ARF to elicit an anti-proliferative response. Such a model explains why loss of ARF or p53 confers similar advantages during Myc-induced tumorigenesis but not following treatment with DNA-damaging drugs such as curcumin. Here, drug resistance is an unselected trait conferred by p53 mutations that provides a unique advantage as the tumor encounters a new environment (e.g., chemotherapy).