Research Perspective Volume 3, Issue 1 pp 26—32

Figure 1. TRF2-ATM-p53 positive feedback loop. TRF2 interacts with ATM and inhibits its autophosphorylation and activation (blue line) [12,13]. ATM phosphorylates and activates p53 (green line) [23,24]. p53 transactivates Siah1, which targets TRF2 for ubiquitination and degradation (red lines) [27]. These regulatory mechanisms form a positive feedback loop. Mutant p53 abrogates this feedback loop through dominant-negative inhibition of wild-type p53 and a gain-of-function activity to inhibit ATM [48]. Δ133p53, a natural p53 isoform, also inhibits wild-type p53 [26]. The other factors that may functionally interact with this feedback loop (β-catenin, p19/p14ARF and MDM2) are also shown. P, phosphorylation. Ub, ubiquitination. Although ATM-mediated phosphorylation of Siah1 inhibits its interaction with a target protein (HIPK2) [36], it is unknown whether this mode of inhibition occurs for TRF2.