Coordination of miR-192 and miR-22 in p53-Mediated Cell Fate Decision

Abstract

p53-targeted microRNAs (miRNAs) markedly affect cellular response to DNA damage. These miRNAs may contribute to either cell cycle arrest or apoptosis induction. However, how these miRNAs coordinate to modulate the decision between cell survival and death remains less understood. Here, we developed an integrated model of p53 signaling network to investigate how p53-targeted miR-192 and miR-22 modulate cellular outcome in response to DNA damage. By numerical simulations, we found that p53 is activated progressively depending on the extent of DNA damage. Upon moderate damage, p53 rises to medium levels and induces miR-192 to promote its own activation, facilitating p21 induction and cell cycle arrest. Upon severe damage, p53 reaches high levels and is fully activated due to phosphatase and tensin homolog (PTEN) induction. As a result, it transactivates miR-22 to repress p21 expression and activate E2F1, resulting in apoptosis. Therefore, miR-192 promotes primary activation of p53, while miR-22 promotes apoptosis by downregulating p21. This work may advance the understanding of the mechanism for cell fate decision between life and death by p53-inducible miRNAs.

New signatures of poor CD4 cell recovery after suppressive antiretroviral therapy in HIV-1-infected individuals: involvement of miR-192, IL-6, sCD14 and miR-144

“…In line with our results, miR-192 has been reported to inhibit cell proliferation and induce apoptosis in vitro 39,40 and rheumatoid arthritis 41 . Also, p53 can induce miR-192 to promote its activation facilitating cell cycle arrest 42,43 . Besides, downregulation of miR-140 has been correlated with higher levels of inflammatory factors in vitro 44 and its upregulation correlated to low levels of IL-6 among other inflammation cytokines 45 .…”

Dual roles of SIRT1 in the BAX switch through the P53 module: A mathematical modeling study

“…Indeed, apoptotic cells accompanied by a sudden burst increase in the concentration of P53 have been experimentally found in the MCF7 cell line treated with doxorubicin [56] , which is in line with our model. Furthermore, the two-phase dynamics pattern of P53 has also been widely mentioned in theoretical and experimental studies [15] , [16] , [56] , [57] . In our model, the appearance of the second-phase P53 dynamics depends on the interplay between the P53 module and the BAX switch.…”

“…The equation forms of P53 are slightly complicated due to the enzymatic reactions, which follow Michaelis–Menten kinetics [15] , [16] . The first term on the right side of Eq.…”

“…Referring to the equations for P53 and SIRT1, the equations of MDM2 are easy to understand. In particular, the P53-dependent synthesis of MDM2 is expressed as a Hill function [15] , [16] , such as the second term of Eq. 7 .…”

“…One of the characteristics of cancer cells is resistance to apoptosis; thus, there is no doubt that the BAX switch is an essential target for tumor treatment [14] . Typically, in response to DNA damage stimuli, the P53 module acts as a sensor to transmit proapoptotic signals to the downstream effector, i.e., apoptotic module [12] , [13] , [15] , [16] , [17] . Although there are other upstream and downstream proteins on the BAX switch [18] , this is beyond the scope of our research and will not be discussed.…”