FIGURE 3.

The updated look at the p53-MDM2-ARF functional complex. Both MDM2 and ARF mediate a variety of p53-independent functions to regulate tumorigenesis. These functions can be either synergistic with or antagonizing against p53-medaited tumor-suppressive activities. Due to the negative feedback loop, the oscillatory relationship between MDM2 and p53 dictates the intensity and duration of p53-mediated tumor-suppressive activities. The outcome of the oscillation depends on their respective expression and activity levels, which are influenced by genetic alterations such as SNP and mutations. Paradoxically, MDM2 sometimes exhibits anti-tumorigenic activity by inhibiting mutant p53 (mutp53) functions, inhibiting pro-tumorigenic factors upon p53 activation, or inducing other tumor-suppressive mechanisms like ferroptosis. ARF also possesses tumor-promoting capabilities when protecting cancer cells against specific types of cell death like anoikis, or exhausting functions of tumor-infiltrating lymphocytes (TIL) to promote cancer progression. Created with BioRender.com.