MiR-192-Mediated Positive Feedback Loop Controls the Robustness of Stress-Induced p53 Oscillations in Breast Cancer Cells

Abstract

The p53 tumor suppressor protein plays a critical role in cellular stress and cancer prevention. A number of post-transcriptional regulators, termed microRNAs, are closely connected with the p53-mediated cellular networks. While the molecular interactions among p53 and microRNAs have emerged, a systems-level understanding of the regulatory mechanism and the role of microRNAs-forming feedback loops with the p53 core remains elusive. Here we have identified from literature that there exist three classes of microRNA-mediated feedback loops revolving around p53, all with the nature of positive feedback coincidentally. To explore the relationship between the cellular performance of p53 with the microRNA feedback pathways, we developed a mathematical model of the core p53-MDM2 module coupled with three microRNA-mediated positive feedback loops involving miR-192, miR-34a, and miR-29a. Simulations and bifurcation analysis in relationship to extrinsic noise reproduce the oscillatory behavior of p53 under DNA damage in single cells, and notably show that specific microRNA abrogation can disrupt the wild-type cellular phenotype when the ubiquitous cell-to-cell variability is taken into account. To assess these in silico results we conducted microRNA-perturbation experiments in MCF7 breast cancer cells. Time-lapse microscopy of cell-population behavior in response to DNA double-strand breaks, together with image classification of single-cell phenotypes across a population, confirmed that the cellular p53 oscillations are compromised after miR-192 perturbations, matching well with the model predictions. Our study via modeling in combination with quantitative experiments provides new evidence on the role of microRNA-mediated positive feedback loops in conferring robustness to the system performance of stress-induced response of p53.

miR-192 Is Overexpressed and Promotes Cell Proliferation in Prostate Cancer

“…Although several studies have shown that miR-192 could target YY1, CCNT2, and GATA6 in human cancers, the mechanism of miR-192 in regulating PCa progression remains unclear [28, 29]. In the present study, we performed bioinformatics analysis for miR-192–5p to explore its potential mechanisms in PCa by using its targets.…”

From Endogenous to Synthetic microRNA-Mediated Regulatory Circuits: An Overview

“…Again, the presence of an miRNA sets a threshold on the amount of a TF, Hes1: Hes1-high ES cells commit to the mesodermal fate, whereas Hes1-low ES cells are induced to differentiate as neuron stem cells [67]. Another work by Moore and colleagues [68] dealt with the p53 oscillations observed in breast cancer cells upon DNA damage induction. Their results suggested that this oscillatory behaviour is the outcome of a network of nested FLs where miRNAs tune the amplitude of oscillations [11].…”

Recent progress and open challenges in modeling p53 dynamics in single cells

“…This may include investigating the role of additional feedbacks or modulators of the core p53-MDM2 feedback such as TRIM25 [18,19,47]. Recently, miRNAs have emerged as potential feedback modulators that provide robustness to the p53 response [48]. Moreover, it will be interesting to explore how interacting pathways modulate the dynamics of p53 to cellular stress and how this translates into altered cell fate decisions.…”