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Mammal

p53-Mdm2 network involved in DNA repair

Summary: 

This model is a refined version of the logical model of the p53-mdm2 network described in Fig. 5a of Abou-Jaoudé et al. [1].

The regulatory graph describes the interactions between protein p53, the ubiquitin ligase Mdm2 in its nuclear and cytoplasmic forms, and DNA damage. It relies on biological data taken from literature.

In short, the nuclear component of Mdm2 down-regulates the level of active p53. This occurs both by accelerating p53 degradation through ubiquitination and by blocking the transcriptional activity of p53.

Protein p53 plays a dual role. It activates the expression of Mdm2 thereby up-regulating the level of cytoplasmic Mdm2, and down-regulates the level of nuclear Mdm2 by inhibiting Mdm2 nuclear translocation through inactivation of the kinase Akt.

DNA damage has a negative influence on the level of nuclear Mdm2, by accelerating its degradation through ATM-mediated phosphorylation and auto-ubiquitination.

Damage-induced Mdm2 destabilization enables p53 to accumulate and remain active.

Finally, high levels of p53 promote damage repair by inducing the synthesis of DNA repair proteins.


model network


References

Curation
Submitter: 
Pedro T. Monteiro

Primary sex determination of chicken gonads

Summary: 

This logical model assembles the current knowledge on the regulation of primary sex determination in chicken. Relying on experimental data, a gene network was constructed, leading to a logical model that integrates both the Z-dosage and dominant W hypotheses. The model showed that the sexual fate of chicken gonads results from the resolution of the mutual inhibition between DMRT1 and FOXL2; the initial amount of DMRT1 product determines the development of the gonads. In this respect, the W-factor functions at the initiation step as a second device, by reducing the amount of DMRT1 in ZW gonads when the sexual fate of the gonad is settled; i.e. when SOX9 functional state is determined. Developmental constraints that are instrumental in this resolution were identified. These constraints correspond to qualitative restrictions regarding the relative transcription rates of the genes DMRT1, FOXL2 and HEMGN. The model further clarified the role of oestrogen in maintaining FOXL2 function during ovary development.

Curation
Submitter: 
C. Chaouiya

Lymphoid and myeloid cell specification and transdifferentiation

Summary: 

Blood cells are derived from a common set of hematopoietic stem cells, which differentiate into more specific progenitors of the myeloid and lymphoid lineages, ultimately leading to differentiated cells. This developmental process is controlled by a complex regulatory network involving cytokines and their receptors, transcription factors and chromatin remodelers.
Based on public and novel data from molecular genetic experiments (qPCR, western blots, EMSA), along with genome-wide assays (RNA-seq, ChIP-seq), we defined a logical model recapitulating cytokine-induced differentiation of common progenitors, the effect of various reported gene knock-downs, as well as reprogramming of pre-B cells into macrophages induced by ectopic expression of specific transcription factors.

Regulatory graph

Note: This model is also available at BioModels database BioModels ID: 1610240000.

Curation
Submitter: 
C. Chaouiya (D. Thieffry)

Boolean model of geroconversion

Summary: 

Altered molecular responses to insulin and growth factors (GF) are responsible for late-life shortening diseases such as type-2 diabetes mellitus (T2DM) and cancers. We have built a network of the signaling pathways that control S-phase entry and a specific type of senescence called geroconversion. We have translated this network into a Boolean model to study possible cell phenotype outcomes under diverse molecular signaling conditions. In the context of insulin resistance, the model was able to reproduce the variations of the senescence level observed in tissues related to T2DM's main morbidity and mortality. Furthermore, by calibrating the pharmacodynamics of mTOR inhibitors, we have been able to reproduce the dose-dependent effect of rapamycin on liver degeneration and lifespan expansion in wild-type and HER2–neu mice. Using the model, we have finally performed an in silico prospective screen of the risk–benefit ratio of rapamycin dosage for healthy lifespan expansion strategies. We present here a comprehensive prognostic and predictive systems biology tool for human aging.

Curation
Submitter: 
Claudine Chaouiya (with Laurence Calzone)

HSPCs-MSCs. Communication pathways between Hematopoietic Stem Progenitor Cells (HSPCs) and Mesenchymal Stromal Cells (MSCs)

Summary: 

Lineage fate decisions of hematopoietic cells depend on intrinsic factors and extrinsic signals provided by the bone marrow microenvironment, where they reside. Abnormalities in composition and function of hematopoietic niches have been proposed as key contributors of acute lymphoblastic leukemia(ALL) progression. Our previous experimental findings strongly suggest that pro-inflammatory cues contribute to mesenchymal niche abnormalities that result in maintenance of ALL precursor cells at the expense of normal hematopoiesis. Here, we propose a molecular regulatory network interconnecting the major communication pathways between hematopoietic stem and progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs) within the bone marrow. Dynamical analysis of the network as a Boolean model reveals two stationary states that can be interpreted as the intercellular contact status.
Furthermore, simulations describe the molecular patterns observed during experimental proliferation and activation. Importantly, our model predicts instability in the CXCR4/CXCL12 and VLA4/VCAM1 interactions following microenvironmental perturbation due by temporal signaling from Toll like receptors (TLRs) ligation. Therefore, aberrant expression of NF-κB induced by intrinsic or extrinsic factors may contribute to create a tumor microenvironment where a negative feedback loop inhibiting CXCR4/CXCL12 and VLA4/VCAM1 cellular communication axes allows for the maintenance of malignant cells.

Curation
Submitter: 
C. Chaouiya (with J. Enciso)

Primary sex determination of placental mammals

Summary: 

Background
Primary sex determination in placental mammals is a very well studied developmental process. Here, we aim to investigate the currently established scenario and to assess its adequacy to fully recover the observed phenotypes, in the wild type and perturbed situations. Computational modelling allows clarifying network dynamics, elucidating crucial temporal constrains as well as interplay between core regulatory modules.
Results
Relying on a comprehensive revision of the literature, we define a logical model that integrates the current knowledge of the regulatory network controlling this developmental process. Our analysis indicates the necessity for some genes to operate at distinct functional thresholds and for specific developmental conditions to ensure the reproducibility of the sexual pathways followed by bi-potential gonads developing into either testes or ovaries. Our model thus allows studying the dynamics of wild type and mutant XX and XY gonads. Furthermore, the model analysis reveals that the gonad sexual fate results from the operation of two sub-networks associated respectively with an initiation and a maintenance phases. At the core of the process is the resolution of two connected feedback loops: the mutual inhibition of Sox9 and ß-catenin at the initiation phase, which in turn affects the mutual inhibition between Dmrt1 and Foxl2, at the maintenance phase. Three developmental signals related to the temporal activity of those sub-networks are required: a signal that determines Sry activation, marking the beginning of the initiation phase, and two further signals that define the transition from the initiation to the maintenance phases, by inhibiting the Wnt4 signalling pathway on the one hand, and by activating Foxl2 on the other hand.
Conclusions
Our model reproduces a wide range of experimental data reported for the development of wild type and mutant gonads. It also provides a formal support to crucial aspects of the gonad sexual development and predicts gonadal phenotypes for mutations not tested yet.

Curation
Submitter: 
C. Chaouiya

Cell fate decision network in the AGS gastric cancer cell line (Flobak et al 2015)

Summary: 

This model accounts for cell fate decision network in the AGS gastric cancer cell line. A set of logical equations has been defined, wich recapitulates AGS data observed in cells in their baseline proliferative state. Using the modeling software GINsim, model reduction and simulation compression techniques were applied to cope with the vast state space of large logical models and enable simulations of pairwise applications of specific signaling inhibitory chemical substances. These simulations predicted synergistic growth inhibitory action of five combinations from a total of 21 possible pairs. All predicted non synergic pairs and four of the predicted synergic ones were confirmed in AGS cell growth real-time assays, including known synergic effects of MEK-AKT or MEK-PI3K inhibitions, along with novel synergistic effects of combined TAK1-AKT or TAK1-PI3K inhibitions.

Curation
Submitter: 
D. Thieffry / C. Chaouiya

Molecular Pathways Enabling Tumour Cell Invasion and Migration

Summary: 

Understanding the etiology of metastasis is very important in clinical perspective, since it is estimated that metastasis accounts for 90% of cancer patient mortality. Metastasis results from a sequence of multiple steps including invasion and migration. The early stages of metastasis are tightly controlled in normal cells and can be drastically affected by malignant mutations; therefore, they might constitute the principal determinants of the overall metastatic rate even if the later stages take long to occur. To elucidate the role of individual mutations or their combinations affecting the metastatic development, a logical model has been constructed that recapitulates published experimental results of known gene perturbations on local invasion and migration processes, and predict the effect of not yet experimentally assessed mutations. The model has been validated using experimental data on transcriptome dynamics following TGF-β-dependent induction of Epithelial to Mesenchymal Transition in lung cancer cell lines. A method to associate gene expression profiles with different stable state solutions of the logical model has been developed for that purpose. In addition, we have systematically predicted alleviating (masking) and synergistic pairwise genetic interactions between the genes composing the model with respect to the probability of acquiring the metastatic phenotype. We focused on several unexpected synergistic genetic interactions leading to theoretically very high metastasis probability. Among them, the synergistic combination of Notch overexpression and p53 deletion shows one of the strongest effects, which is in agreement with a recent published experiment in a mouse model of gut cancer. The mathematical model can recapitulate experimental mutations in both cell line and mouse models. Furthermore, the model predicts new gene perturbations that affect the early steps of metastasis underlying potential intervention points for innovative therapeutic strategies in oncology.

Curation
Submitter: 
L. Calzone / C. Chaouiya

Multilevel mammalian cell cycle model

Summary: 

This model is an extension of the seminal model of the G1/S restriction point control of mammalian cell cycle, published by Fauré et al (2006) [1]. We have used model-checking and computing tree logics (CTL) to progressively refine Fauré's model in order to fit recent experimental observations. The resulting model accounts for the sequential activation of cyclins, the role of Skp2, and emphasizes a multifunctional role for the cell cycle inhibitor Rb.
We provide the models in different formats:
1) An archive containing the multilevel model, to be open with GINsim (v2.9.3).
2) An archive containing a Boolean translation of this model, to be open with GINsim (v2.9.3).
3) A SBML Qual export of the multilevel model.
4) A SBML Qual export of the Boolean version.
Furthermore, we provide a script containing the main NuSMV queries used in the article describing the methodology and the resulting revised model.


References

Curation
Submitter: 
Pedro T. Monteiro

Mutually exclusive and co-occurring genetic alterations in bladder tumorigenesis

Summary: 

Relationships between genetic alterations, such as co-occurrence or mutual exclusivity, are often observed in cancer, where their understanding may provide new insights into etiology and clinical management. In this study, we combined statistical analyses and computational modelling to explain patterns of genetic alterations seen in 178 patients with bladder tumours (either muscle-invasive or non-muscle-invasive). A statistical analysis on frequently altered genes identified pair associations including co-occurrence or mutual exclusivity. Focusing on genetic alterations of protein-coding genes involved in growth factor receptor signalling, cell cycle and apoptosis entry, we complemented this analysis with a literature search to focus on nine pairs of genetic alterations of our dataset, with subsequent verification in three other datasets available publically. To understand the reasons and contexts of these patterns of associations while accounting for the dynamics of associated signalling pathways, we built a logical model. This model was validated first on published mutant mice data, then used to study patterns and to draw conclusions on counter-intuitive observations, allowing one to formulate predictions about conditions where combining genetic alterations benefits tumorigenesis. For example, while CDKN2A homozygous deletions occur in a context of FGFR3 activating mutations, our model suggests that additional PIK3CA mutation or p21CIP deletion would greatly favour invasiveness. Further, the model sheds light on the temporal orders of gene alterations, for example, showing how mutual exclusivity of FGFR3 and TP53 mutations is interpretable if FGFR3 is mutated first. Overall, our work shows how to predict combinations of the major gene alterations leading to invasiveness.

Curation
Submitter: 
Claudine Chaouiya
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