Modeling the role of microRNA-449a in the regulation of the G2/M cell cycle checkpoint in prostate LNCaP cells under ionizing radiation

Abstract

Recent studies showed that induced microRNA-449a (miR-449a) enhances a G2/M cell cycle checkpoint arrest in prostate cancer (LNCaP) and lung adenocarcinoma cell lines. In the case of LNCaP cells, upregulated miR-449a directly downregulates c-Myc that is required to induce the cell cycle regulators Cdc25A and Cdc2/CyclinB whose inactivation blocks G2 to M phase transition. However, the molecular mechanisms involved are yet unclear, although in other prostate cancer cells the interactions among p53, miR-449a and Sirt-1 can affect the induction of the G2/M arrest. In order to clarify these molecular mechanisms, in this work we propose a boolean model of the G2/M checkpoint arrest regulation contemplating the influence of miR-449a. The model shows that the cell fate determination between two cellular phenotypes: G2/M-Arrest for DNA repair and G2/M-induced apoptosis is stochastic and influenced by miR-449a state of activation. The results were compared with experimental data available presenting agreement. We also found that several feedback loops are involved in this cell fate regulation and we indicate, through in silico gain or loss of function perturbations of genes, which of these feedback loops are more efficient to favor a specific phenotype.

Dynamics of the feedback loops required for the phenotypic stabilization in the epithelial‐mesenchymal transition

“…Models are constantly being produced to elucidate the dynamics of complex biological systems . In the EMT context, Tian et al proposed a mathematical model consisting of ‘Cascading Bistable Switches’ (CBS) .…”

Integrative data modeling from lung and lymphatic cancer predicts functional roles for miR-34a and miR-16 in cell fate regulation

“…Activated p53 triggers transcription of E3 ubiquitin protein ligase (Mdm2) 27 . In the model, based on the different phosphorylation states that p53 possess, it is further represented by two other variables: p53-A and p53-K. P53-A represents p53 phosphorylated at serine 15 and serine 20, whereas p53-K describes an additional phosphorylation at serine 46 (for more details about p53-A/ p53-K function see 7,28 ). P21, protein phosphatase, Mg2 + /Mn2 + dependent 1D (Wip1) and tumor protein p53 inducible nuclear protein 1 (TP53-INP1) are activated by p53-A.…”

“…In the present study we model the regulatory role and synergistic action 1 of miR-16 and miR-34a in the G1/S cell cycle checkpoint using Boolean methods [7][8][9][10] .…”

Hyperactivation of the p53–MicroRNA Signaling Pathway: Mathematical Model of Variants of Antitumor Therapy

“…В [60] представлены развивающие подход [61] результаты исследований последних лет, в том числе -анализ регуляторной функции факторов транскрипции и микроРНК в процессах, определяющих судьбу клетки. В [62] построена булева модель и на ее основе выполнено исследование роли miR-449a в регуляции клеточного цикла и апоптоза под действием ионизирующего излучения. Молекулярная модель [62] интересна тем, что она описывает во взаимодействии сразу два чувствительных к стрессу механизма -активацию p53 и активацию miR-449a в ответ на повреждение ДНК.…”

“…В [62] построена булева модель и на ее основе выполнено исследование роли miR-449a в регуляции клеточного цикла и апоптоза под действием ионизирующего излучения. Молекулярная модель [62] интересна тем, что она описывает во взаимодействии сразу два чувствительных к стрессу механизма -активацию p53 и активацию miR-449a в ответ на повреждение ДНК. Предполагается, что в каждом из этих механизмов задействован Sirt1: функциональность Sirt1 непосредственно контролируется miR-449a, и это может косвенно повлиять на динамику p53.…”