Cancer is the second leading cause of death in the United States, and it results from genetic alterations that promote the survival and proliferation of neoplastic cells. One of the most commonly disrupted cancer gene networks is the ARF-Mdm2-Tip60-p53 pathway. Inactivation of the ARF, Tip60 and p53 tumor suppressors and/or overexpression of the Mdm2 oncogene occurs in most, if not all, human cancers. An improved molecular understanding of that pathway, especially how it becomes activated, is expected to advance the development of innovative therapeutics aimed at restoring its function in tumors. Our group originally discovered NIAM (Nuclear Interactor of ARF and Mdm2) as a novel binding partner of ARF that has several functional ties to Mdm2 and p53. Early studies showed that NIAM is negatively regulated by Mdm2, can collaborate with ARF to block cell proliferation, and is a new activator of p53-mediated transcription. NIAM could also act independent of those factors to suppress cell proliferation and promote chromosomal stability, and microarray studies suggested its expression is significantly reduced in many human cancers. Those findings led us to speculate that NIAM is a tumor suppressor that functions in both the ARF-Mdm2-p53 pathway as well as other undefined anti-cancer pathways. My thesis research explored two different aspects of that hypothesis: 1) how does NIAM activate p53, and 2) is NIAM a tumor suppressor? Initial work showed that NIAM could stimulate p53 independently of ARF, the major activator of p53, indicating that other factors must be required. My studies revealed that NIAM indirectly promotes p53 activation through functional interactions with two other p53 regulators, Tip60 and Mdm2. Tip60 is an acetyltransferase that activates p53 through direct association on p53 target promoters as well as acetylation of p53 at lysine 120 (K120). I found that NIAM can induce K120 acetylation of p53; however, NIAM's association with Tip60 (not the acetylation of p53) was essential for maximal p53 transcriptional activation. Mdm2, the major antagonist of p53, is an E3 ubiquitin ligase that promotes p53 ubiquitylation and degradation. I found that NIAM disrupts Mdm2-p53 complexes and blocks p53 ubiquitylation, thereby interfering with p53 inhibition by Mdm2. Thus, NIAM regulates two critical pathways that control p53 function and are altered in human cancers, implying an important role for NIAM in tumorigenesis. To test that idea directly, we generated NIAM gene-trap knockout mice (hypomorphs) that expressed greatly reduced yet detectable levels of NIAM in all tissues. Fifty percent of the NIAM knockout mice developed benign and early stage cancers, including B-cell lymphoma, whereas all age-matched control animals were tumor-free. These results showed that NIAM loss causes increased susceptibility to tumorigenesis. In sum, my work suggests a significant role for NIAM in p53 control and tumor biology. Additional studies will be needed to determine which physiological or pathological signals normally engage NIAM to promote p53 function and suppress tumor development. It is anticipated that the NIAM knockout mice will provide an outstanding platform to interrogate NIAM's biological role in cancer, particularly in ARF-Mdm2-Tip60-p53 signaling as well as other pathways affecting genome maintenance. Ultimately, insights gained from such studies may justify novel therapies that seek to restore NIAM activity in tumors.

Ce travail de thèse se place dans le cadre d'une convention université/industrie de type CIFRE entre le CRAN et la scierie Siat-Braun. Le processus de transformation d'une scierie est divisé en deux parties. Tout d'abord, le parc à grumes tronçonne une grume en billons (bois ronds de longueur standard) qui sont triés en lots homogènes en dimensions et qualité. Ensuite, la ligne de sciage transforme ces billons en produits finis (sciages) également triés par dimensions et qualité. Le tri qualitatif des billons ayant une influence directe sur la qualité des produits finis vendus, les scieries visent à optimiser cette étape afin de réduire le taux de déclassement des produits finis. Dans cet objectif, la scierie Siat-Braun a investi dans un nouveau parc à grumes. Les travaux de cette thèse contribuent au développement et à la mise en oeuvre de ce système dédié au tri Qualité des billons. Le premier chapitre de ce mémoire positionne le projet dans la filière Bois puis explicite les contraintes et les besoins d'une scierie en termes de Qualité. Une étude bibliographique met en évidence les différents systèmes d'observation permettant la mesure des caractéristiques du bois dans le but de faire un classement qualité, aussi bien des billons que des produits finis. Le système d'observation choisi par notre partenaire industriel est ensuite présenté. L'objectif de la seconde partie du mémoire est d'expliciter et de définir la Qualité Billons pour le nouveau système de tri. Cette notion de qualité étant détenue par les opérateurs de tri, nous avons proposé d'extraire, de formaliser et de modéliser cette connaissance en utilisant la méthode NIAM-ORM. Cette méthode a permis d'obtenir deux ontologies structurées : la Qualité Billon et la Qualité Sciage que nous avons exploitées dans le chapitre 3 afin de mettre en avant 50 liens entre les deux qualités généralement appréhendées séparément. Cette étude a également permis d'extraire 34 critères pertinents pour spécifier la Qualité Billon en 9 classes, au regard de la Qualité Sciage. De plus, l'exploitation des modèles de connaissance fournit un paramétrage initial pour la mise en service du système d'observation (critères d'entrée, classes de sortie, seuils de décision). Ce paramétrage est alors éprouvé lors des premières exploitations. Les premiers tests sur les produits finis et l'exploitation des données délivrées par le capteur nous servent à valider et à affiner le paramétrage pour améliorer le classement des billons en fonction de la qualité des produits finis obtenus. Ces travaux de thèse ont donc permis de capitaliser la connaissance Experte des acteurs du projet puis d'obtenir une configuration initiale pertinente pour la première mise en service du système de tri. Les premières analyses ont permis d'améliorer le paramétrage du système de tri Qualité Billon. Dans un futur proche, nous envisageons d'approfondir l'analyse des données fournies par le système afin d'améliorer la sélection des critères pertinents / This study takes place in the frame of a university/industry convention between the CRAN and Siat-Braun sawmill. Sawmill transformation process is divided in two parts. First, the log yard cuts down stem in logs (round timber with standard length) which are sorted out in homogeneous batches by dimensions and quality. Then, the sawing line transforms those logs in end products sorted out by dimensions and quality too. The qualitative sort out of log has a direct impact on sold product quality, so sawmills try to optimize this production step in order to reduce the product downgrading rate. In this goal, Siat-Braun sawmill invested in a new log yard. This study contributes to the development and the commissioning of this system dedicated to log Quality sort out. The first chapter of this thesis places the project into wood industry then explicates sawmill constraints and needs in term of Quality. A literature review points out different observation systems allowing measurement of wood characteristics in order to make a product and log quality rankings. Observation system chosen by our industrial partner is then presented. The objective of the second chapter is to clarify and defines Log Quality to the new log yard. This quality notion being held by the sorting operator, we suggested extract, formalize and model this knowledge using NIAM-ORM method. This method allowed obtaining two structured ontologies: the Log Quality and the Product Quality which we used in the chapter three in order to underlying 50 links between both qualities usually tackle separately. This study allowed also extracting 34 relevant criteria to specify Log Quality in 9 classes, regarding Product Quality. In addition, knowledge model analysis gives an initial set up to the first commissioning of the Observation system (input criteria, output classes, decision thresholds). This set up is so proven during system exploitation. The first tests on end products and data processing delivered by the sensor are used to validate and refine the set up to improve the log sort out regarding the obtained product quality. So, this study allowed capitalizing Expert knowledge of the project actors and then, obtaining a relevant initial configuration of the sort system for the first use. First analysis allowed improving Log Quality sort out system set up. In a near future, we want to go deeper in analysis of data given by the system in order to improve relevant criteria selection

In the development of information systems for business, structured approaches are widely used in practice. Structured approaches provide a prescription and guidelines for how to go about the process of developing an information system, are relatively easy to learn and provide tools which are well suited to their task. However, the products of structured approaches are sometimes seen to be vague and imprecise since requirements are written using natural language or represented in the form of models which do not have a formal foundation. This vagueness or ambiguity can be the source of problems later in development of the information system. A possible solution to this is to represent requirements using formal methods since these are seen as precise and unambiguous. However, formal methods are typically only a mathematical language for representing requirements. They are often regarded as difficult to learn and use. Even though formal methods of one sort or another have been in existence for many years they are not popular and appear unlikely to become popular in the future. One possible approach to providing the advantages of structured approaches and formal methods is to provide translation procedures from the products of structured approaches to a formal description in a suitable formal language. The work in this thesis follows this theme and is aimed at the creation of a translation procedure from an Object Role Model (ORM) schema to a Z specification. An object role model schema is the end product of a process called the Natural Language Information Analysis Method (NIAM) which is used to produce an information model for an information system. NIAM is a method which has been used successfully in industry since the mid 1970s and continues to be used today. This thesis provides a translation procedure from ORM to Z which is less arbitrary and more comprehensive than previous conversion procedures in the literature. It establishes a systematic method for (i) choosing suitable types and variables for a Z specification and (ii) predicates that express all the standard constraints available in ORM modelling. The style of representation in Z preserves ORM�s concepts in a way that aids traceability and validation. The natural language basis of ORM, namely the use of elementary facts, is preserved. Furthermore, an ORM schema differentiates between abstract concepts and the means by which these concepts are represented symbolically and this thesis provides a representation in Z that maintains the distinction between conceptual objects and their symbolic representation. Identification schemes of entity types are also translated into the Z specification but it is left as an option in the translation procedure. Guiding and evaluating the work conducted here are a published set of criteria for the evaluation of a conceptual schema. These have helped in making decisions regarding the translation procedure and for assessing my work and that of others.