MiR-192-Mediated Positive Feedback Loop Controls the Robustness of Stress-Induced p53 Oscillations in Breast Cancer Cells
Fig 2
Diagram of the p53-MDM2 oscillator under the regulation of positive feedbacks via microRNA-192, -34a and -29a.
p53 is translated from p53 mRNA and remains inactive. Phosphorylated by ATM*, p53 becomes active (p53*), and able to transcribe mdm2 mRNA. MDM2 protein, translated from mdm2 mRNA, promotes a fast degradation of p53 and a slow degradation of p53*. In addition to a basal self-degradation, MDM2 is degraded by a mechanism stimulated by ATM*. The three microRNAs, miR-192, miR-34a and miR-29a, are induced by p53*, and inhibit the mRNAs of mdm2, cdc42, wip1, sirt1 and yy1, whose protein products further regulate p53* and MDM2. Specifically, the microRNA binds with its target mRNA molecule with high affinity, forming a microRNA-mRNA complex, and subsequently dispose the complex into a degradation machinery. In other words, the microRNAs in our model are assumed to enhance the degradation of their mRNA target by complexation and subsequent disposal. In particular, CDC42, Wip1 and SIRT1 proteins deactivate p53 directly, while YY1 enhances the MDM2-dependent degradation of p53 and p53* proteins. In addition, Wip1 protein inhibits the degradation of MDM2 protein. The wip1 mRNA is also induced by p53*, whose protein product inhibits active ATM, forming a second negative feedback loop.