RÉSUMÉ
The mechanisms leading to the cell fate decision between apoptosis and senescence upon DNA damage are still unclear and have stochastic features. Cellular oxidative stress can generate DNA damage and activate the important mitogen-activated protein kinase 14 (p38MAPK) that is involved in pathologies like Alzheimer's disease. Based on experimental evidence we propose a simple network that might operate at the core of the cell control machinery for the choice between apoptosis and senescence involving the cross-talk between p38MAPK, the tumor suppressor protein p53 and the cyclin-dependent kinase inhibitor (p16INK4a). We have performed two types of analyses, deterministic and stochastic, exploring the system's parameter space, in the first, we calculated the fixed points of the deterministic model and, in the second, we numerically integrated the master equation for the stochastic version. The model shows a variety of behaviors dependent on the parameters including states of high expression levels of p53 or p16INK4a that can be associated with an apoptotic or senescent phenotype, respectively, in agreement with experimental data. In addition, we observe both monostable and bistable behavior (where bistability is a phenomenon in which two stable steady states coexist for a fixed set of control parameter values) which here we suggest to be involved in the cell fate decision problem.
Sujet(s)
Apoptose , Vieillissement de la cellule , Inhibiteur p16 de kinase cycline-dépendante/métabolisme , Modèles biologiques , Protéine p53 suppresseur de tumeur/métabolisme , p38 Mitogen-Activated Protein Kinases/métabolisme , Altération de l'ADN , Cinétique , Espèces réactives de l'oxygène/métabolisme , Reproductibilité des résultats , Processus stochastiquesRÉSUMÉ
In general, stochastic tumors show genomic instability associated with the proliferation of DNA point mutations, that is, a mutator phenotype. This feature cannot be explained by a dysfunctional mismatch repair alone, and indicates that nucleotide excision repair (NER) and/or base excision repair should be suppressed. However, mutations in NER genes are not causally implicated in the oncogenesis of sporadic solid tumors, according to the Cancer Gene Census at http://www.sanger.ac.uk/genetics/CGP/Census/. This brings up an apparent paradox: how to explain the recurrent non-existence in NER genes of somatic mutations causally related to cancer? In a recent study, we have shown that the origin of point mutations in cancer cell genomes can be explained by a structurally conserved NER with a functional disorder generated from its entanglement with a disabled apoptosis gene network. In the present study, we further characterize NER gene network properties and show that it has a highly connected architecture. This feature suggests that the absence of mutations in NER genes in sporadic solid tumors is a result of their participation in many essential cellular functions.
Sujet(s)
Réparation de l'ADN/génétique , Réseaux de régulation génique , Tumeurs/génétique , Mutation ponctuelle , Apoptose/génétique , Instabilité du génome , HumainsRÉSUMÉ
In general, stochastic tumors show genomic instability associated with the proliferation of DNA point mutations, that is, a mutator phenotype. This feature cannot be explained by a dysfunctional mismatch repair alone, and indicates that nucleotide excision repair (NER) and/or base excision repair should be suppressed. However, mutations in NER genes are not causally implicated in the oncogenesis of sporadic solid tumors, according to the Cancer Gene Census at http://www.sanger.ac.uk/genetics/CGP/Census/. This brings up an apparent paradox: how to explain the recurrent non-existence in NER genes of somatic mutations causally related to cancer? In a recent study, we have shown that the origin of point mutations in cancer cell genomes can be explained by a structurally conserved NER with a functional disorder generated from its entanglement with a disabled apoptosis gene network. In the present study, we further characterize NER gene network properties and show that it has a highly connected architecture. This feature suggests that the absence of mutations in NER genes in sporadic solid tumors is a result of their participation in many essential cellular functions.
Sujet(s)
Humains , Réseaux de régulation génique , Tumeurs/génétique , Mutation ponctuelle , Réparation de l'ADN/génétique , Apoptose/génétique , Instabilité du génomeRÉSUMÉ
The description of the complex molecular network responsible for cell behavior requires new tools to integrate large quantities of experimental data in the design of biological information systems. These tools could be used in the characterization of these networks and in the formulation of relevant biological hypotheses. The building of an ontology is a crucial step because it integrates in a coherent framework the concepts necessary to accomplish such a task. We present MONET (molecular network), an extensible ontology and an architecture designed to facilitate the integration of data originating from different public databases in a single- and well-documented relational database, that is compatible with MONET formal definition. We also present an example of an application that can easily be implemented using these tools.
Sujet(s)
Bases de données génétiques , Biologie informatique/méthodes , Biologie moléculaire , Intégration de systèmes , Réseaux de communication entre ordinateursRÉSUMÉ
We present the MOlecular NETwork (MONET) ontology as a model to integrate data from different networks that govern cell function. To achieve this, different existing ontologies were analyzed and an integrated ontology was built in a way to make it possible to share and reuse knowledge, support interoperability between systems, and also allow the formulation of hypotheses through inferences. By studying the cell as an entity of a myriad of elements and networks of interactions, we aim to offer a means to understand the large-scale characteristics responsible for the behavior of the cell and to enable new biological insights.