Mathematical modelling for the functioning of the p53 signaling pathway following DNA damage. I. The model of activation of the p53-Mdm2-Wip1 system

2021 ◽  
pp. 33-53
Author(s):  
Ольга Фалалеевна Воропаева ◽  
Ксения Сергеевна Гаврилова
Keyword(s):  
Dna Damage ◽  
Signaling Pathway ◽  
Initial Conditions ◽  
P53 Protein ◽  
Special Role ◽  
Degenerative Diseases ◽  
Simple Modification ◽  
P53 Signaling ◽  
Wide Range ◽  
P53 Signaling Pathway

Работа посвящена численному исследованию известной математической модели динамики системы p53-Mdm2-Wip1 при различных воздействиях, приводящих к повреждениям ДНК. Главное внимание уделено ранее не рассматривавшимся методическим аспектам - оценке чувствительности модели, качественному анализу свойств решения в биологически адекватном диапазоне значений параметров, анализу применимости модели к описанию критических состояний системы, связанных с известными дегенеративными заболеваниями. Показано, что простейшая модификация исходной модели делает ее существенно более эффективным инструментом для численного анализа широкого диапазона состояний системы p53-Mdm2-Wip1 In the context of the survival and death of cells with DNA damage, a special role is assigned to the p53 protein. The management of p53 and its inhibitors can provide a protective effect in a wide range of degenerative diseases, such as cancer, infarctions, and dementia. Therefore, there are increased requirements for mathematical models designed to study the mechanism of functioning of the p53 signaling pathway. Our work is devoted to the study of the properties of the well-known mathematical model of the dynamics of the p53-Mdm2-Wip1 system under various influences leading to DNA damage. A simple modification of the model is proposed. The main attention is paid to the analysis of the sensitivity and qualitative properties of solutions, as well as the validation of the model before and after its modification. In numerical experiments, it was found that within the framework of the accepted models, the stationary state of the p53-Mdm2-Wip1 system can be unstable to negligible changes in the initial conditions, so that the system can function under the same parameter values according to the bifurcation scenario with a doubling of the period. The mathematical conditions under which the multiplicity of solutions and complex dynamic modes were detected allow for a biological interpretation as a reflection of the variability in the response of the p53 protein pathway to the damage signal. The range of applicability of the models was compared using the example of a wellknown laboratory experiment, in which the most complete set of observed in vitro and in vivo states of the p53-Wip1 system was demonstrated when irradiating cancer cells with wild-type p53. It is shown that the simplest modification of the original model significantly expands the scope of its applicability, allows describing the transition from normal to critical states of the system associated with known degenerative diseases. Thus, the modified model is a more effective tool for numerical analysis of a wide range of states of the p53-Mdm2-Wip1 system

Dysregulation, But Not Mutation Of p53 Signaling Pathway In Breast Implant-Associated Anaplastic Large Cell Lymphoma Cell Lines

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4879-4879 ◽  
Author(s):  
Hai Wang ◽  
Chao Xie ◽  
Shiwu Li ◽  
Eva V. George ◽  
Westley H. Reeves ◽  
...  
Keyword(s):  
Dna Damage ◽  
Signaling Pathway ◽  
Cell Lines ◽  
P53 Protein ◽  
Breast Implant ◽  
Large Cell ◽  
Qrt Pcr ◽  
P53 Signaling ◽  
P53 Activation ◽  
P53 Signaling Pathway

Abstract A consistent feature of over 100 reported cases of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is their complex cytogenetic abnormalities, suggesting that genomic instability may drive lymphomagenesis and/or tumor progression. Loss of heterozygosity(LOH) of the TP53 tumor suppressor gene locus on the short arm of chromosome 17 (17p13.1) is a frequent finding. Human p53 plays an important role in cell cycle arrest, DNA repair, and apoptosis and it maintains genome stability by preventing mutations. Recently, three T cell breast lymphoma (TLBR) cell lines were derived from patients’ BIA-ALCL primary tumor biopsy specimens. These cell lines are IL-2 dependent, ALK-negative, CD30+activated cytotoxic T cells closely resembling the original tumor cells. Thus, the cell lines may serve as an important tool for studying this newly recognized disease entity. Because of its rarity, the clinical pathologic features, tumor cell biology, and genetics of BIA-ALCL have yet to be fully defined. Here we tested the hypothesis that the p53 signaling pathway is defective in TLBR cells. We initially examined TP53 transcript expression among the cell lines. By qRT-PCR, p53 transcripts were detected in all three lines, with the highest level in TLBR-2. Next we examined p53 protein expression and p53 activation in response to ultraviolet (UV) or gamma irradiation. By Western blotting, all TLBR cell lines expressed much lower levels of p53 protein following UV irradiation (400 J/m2) than Karpas (ALK+ ALCL) cells and failed to show ATM/ATR-induced phosphorylation of p53 on serine 15, an early indicator of p53 activation. Genetic defects (deletion, mutation) of the p53 coding sequence were not found by Sanger sequencing. Interestingly, a polymorphism at p53 codon 72 (Arg72Pro), a normal variant associated with increased susceptibility to breast cancer, was detected in TLBR-1 and -3 (derived from indolent BIA-ALCL), but not in the aggressive BIA-ALCL line TLBR-2. Thus, TLBR cells exhibit defective regulation of the p53 pathway in response to DNA damage, suggesting that their ability to sense DNA damage or the regulation of p53 stability may be impaired. We next examined the DNA damage sensing pathway upstream of p53 in the presence and absence of the DNA demethylating agent 5-aza-2'-deoxycytidine (AZA, 10µM for 48hrs). In all TLBR lines, ATM and ATR transcripts were expressed at much lower levels (qRT-PCR) than normal, and their expression was not significantly affected by AZA. However, compared with human T cells, CHK2 (phosphorylate P53 at Ser20) transcripts were very low in TLBR-1 and -2, but not in TLBR-3 cells. CHK2 and p21 (the main p53 target gene) transcripts after AZA were greatly increased in TLBR-2, mildly elevated in TLBR-3, and unchanged in TLBR-1 cells, suggesting that DNA methylation of the CHK2 and p21 genes may partly explain the defective p53 signaling in TLBR-2 cells. This was confirmed by detecting of CHK2 phorphrylation only in TLBR-3 cells. Mdm2, a major negative regulator of p53 protein stability, was either normal or low (qRT-PCR), and was unaffected by AZA. However, immunobloting with Mdm2 antibodies revealed increased levels of two isoforms following UV of TLBR-1 and -2, but only the small isoform was expressed in TLBR-3 cells and there was little response to UV treatment. Treatment of TLBR cells with 5 µM Nutlin-3 (Mdm2 antagonist, p53 activator, and apoptosis inducer) inhibited cell growth by 40% at day 5 (MTT assay). We conclude that these three BIA-ALCL derived cell lines share dysregulation of the p53 signaling pathway, which may contribute to the genomic instability characteristic of these BIA-ALCL cases. First two authors have equally contributed to this abstract. Disclosures: No relevant conflicts of interest to declare.

The Molecular Docking of Flavonoids Isolated from Daucus carota as a Dual Inhibitor of MDM2 and MDMX

2020 ◽  
Vol 15 (2) ◽  
pp. 154-164 ◽  
Author(s):  
Ijaz Muhammad ◽  
Noor Rahman ◽  
Gul E. Nayab ◽  
Sadaf Niaz ◽  
Mohibullah Shah ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cancer Therapy ◽  
Natural Product ◽  
Signaling Pathway ◽  
In Silico ◽  
P53 Protein ◽  
Dual Inhibitor ◽  
P53 Signaling ◽  
In Silico Studies ◽  
P53 Signaling Pathway

Background: Cancer is characterized by overexpression of p53 associated proteins, which down-regulate P53 signaling pathway. In cancer therapy, p53 activity can be restored by inhibiting the interaction of MDMX (2N0W) and MDM2 (4JGR) proteins with P53 protein. Objective: In the current, study in silico approaches were adapted to use a natural product as a source of cancer therapy. Methods: In the current study in silico approaches were adapted to use a natural product as a source of cancer therapy. For in silico studies, Chemdraw and Molecular Operating Environment were used for structure drawing and molecular docking, respectively. Flavonoids isolated from D. carota were docked with cancerous proteins. Result: Based on the docking score analysis, we found that compound 7 was the potent inhibitor of both cancerous proteins and can be used as a potent molecule for inhibition of 2N0W and 4JGR interaction with p53. Conclusion: Thus the compound 7 can be used for the revival of p53 signaling pathway function however, intensive in vitro and in vivo experiments are required to prove the in silico analysis.

Application of minimal mathematical models for the dynamics of the signaling pathway of the p53 - miRNA to the analysis of laboratory data

2021 ◽  
pp. 4-49
Author(s):  
Софья Дмитриевна Сенотрусова ◽  
Ольга Фалалеевна Воропаева ◽  
Юрий Иванович Шокин
Keyword(s):  
Mathematical Models ◽  
Signaling Pathway ◽  
Numerical Solutions ◽  
Laboratory Data ◽  
Minimal Models ◽  
Basic Model ◽  
P53 Signaling ◽  
Wide Range ◽  
P53 Signaling Pathway

Работа посвящена практическому использованию минимальных математических моделей динамики сигнального пути p53 для описания достаточно широкого круга лабораторных экспериментов, в которых взаимодействие p53 и белковингибиторов p53 опосредуется микроРНК, образующими с p53 петлю положительной обратной связи. Представлены базовая модель, разработанные на ее основе новые минимальные модели, алгоритм численного решения прямых и обратных коэффициентных задач и результаты сопоставления полученных численных решений с экспериментальными данными о динамике уровней белков p53, p21, Bax, белков-ингибиторов Mdm2, Wip1, Sirt1 и различных микроРНК (miR-16, miR-34a, miR-192, miR-194, miR-215) в условиях стрессовых воздействий. С привлечением полученных математических моделей исследованы базовые механизмы функционирования сигнального пути p53 в условиях, приближенных к условиям конкретных лабораторных экспериментов in vitro и in vivo. Продемонстрированы синергический эффект гиперактивации сигнального пути p53, в котором задействованы микроРНК, и механизмы бимодального переключения. Показана ключевая роль p53-зависимых микроРНК в реализации некоторых гипотетических терапевтических стратегий, связанных с управлением механизмом активации апоптоза клеток. В рамках принятой базовой модели даны оценки вероятности рассогласования в диагностике дегенеративных заболеваний, основанной на анализе уровня p53зависимых микроРНК и p53, при слабой и умеренной дерегуляции микроРНК. This study addresses the practical use of minimal mathematical models of the dynamics of a hypothetical system of the p53 signaling pathway to describe a fairly wide range of laboratory experiments. In such system, the interaction of p53 and p53 inhibitor proteins is mediated by microRNAs that form a positive feedback loop with p53. A basic model, new minimal models developed on its basis, an algorithm for the numerical solution of direct and inverse coefficient problems, and the results of comparing the obtained numerical solutions with experimental data on the dynamics of the levels of p53, p21, Bax proteins, inhibitor proteins Mdm2, Wip1, Sirt1, and various microRNAs (miR-16, miR-34a, miR-192, miR-194, miR-215) under stress conditions are presented. In numerical experiments, the main mechanisms of the p53 signaling pathway were investigated. A synergistic effect of hyperactivation of the p53 signaling pathway and bimodal switching mechanisms has been demonstrated. We show the key role of p53-dependent microRNAs in the implementation of some hypothetical therapeutic strategies associated with the control mechanism for activation of cells apoptosis. Within the framework of the accepted basic model, we estimated the probability of mismatch in the diagnosis of the patient’s status. The status is based on the analysis of the level of p53-dependent microRNAs and p53, with weak and moderate deregulation of microRNAs.

scholarly journals Folate-targeted PTEN/AKT/P53 signaling pathway promotes apoptosis in breast cancer cells

Pteridines ◽  
2020 ◽  
Vol 31 (1) ◽  
pp. 158-164
Author(s):  
Hexian Wang ◽  
Qiang Fan ◽  
Longlong Zhang ◽  
Danli Shi ◽  
Haibo Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Folic Acid ◽  
Cell Viability ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Breast Cancer Cells ◽  
P53 Protein ◽  
Specific Inhibitor ◽  
P53 Signaling ◽  
P53 Signaling Pathway

AbstractObjective Folate deficiency is closely related to the occurrence of human tumors and plays an important role in cell growth, differentiation, repair, and host defense. We studied the effects of folic acid on the apoptosis of breast cancer cells (MDA-MB-231) and on the activity of the PTEN/AKT/P53 signaling pathway in breast cancer cells.Methods Breast cancer cells (MDA-MB-231) were treated with folate alone or in combination with a PTEN specific inhibitor, SF1670. Cell viability was detected by a MTT assay, and the expression levels of apoptosis-related proteins and PTEN/AKT/P53 signaling pathway were detected via Western blot analysis. Rate of apoptosis was measured via cytometry.Results Folic acid inhibited the cell viability of MDAMB-231 cells and the expressions of Bcl-2 and p-AKT proteins and upregulate the expression of Bax, PTEN, and P53 proteins, thereby inducing apoptosis in these cells. SF1670 treatment inhibited the expressions of Bcl-2 and p-AKT protein and upregulate Bax, PTEN, and P53 protein expression.Conclusion Folic acid has cytotoxic effects on MDAMB-231 cells and can induce apoptosis by targeting the PTEN/AKT/P53 signaling pathway.

Sign in / Sign up

Export Citation Format

Share Document