02784nas a2200301   4500008004100000245006900041210006800110300000800178490000600186520165900192653002501851653002201876653001901898653006101917653007001978653003402048653013602082100001802218700002102236700001702257700002402274700001402298700001402312700001602326700001502342700001902357856010602376       2007                        eng d00aEvidence for systems-level molecular mechanisms of tumorigenesis0 aEvidence for systemslevel molecular mechanisms of tumorigenesis  a1850 v83 aBACKGROUND: Cancer arises from the consecutive acquisition of genetic alterations. Increasing evidence suggests that as a consequence of these alterations, molecular interactions are reprogrammed in the context of highly connected and regulated cellular networks. Coordinated reprogramming would allow the cell to acquire the capabilities for malignant growth. RESULTS: Here, we determine the coordinated function of cancer gene products (i.e., proteins encoded by differentially expressed genes in tumors relative to healthy tissue counterparts, hereafter referred to as "CGPs") defined as their topological properties and organization in the interactome network. We show that CGPs are central to information exchange and propagation and that they are specifically organized to promote tumorigenesis. Centrality is identified by both local (degree) and global (betweenness and closeness) measures, and systematically appears in down-regulated CGPs. Up-regulated CGPs do not consistently exhibit centrality, but both types of cancer products determine the overall integrity of the network structure. In addition to centrality, down-regulated CGPs show topological association that correlates with common biological processes and pathways involved in tumorigenesis. CONCLUSION: Given the current limited coverage of the human interactome, this study proposes that tumorigenesis takes place in a specific and organized way at the molecular systems-level and suggests a model that comprises the precise down-regulation of groups of topologically-associated proteins involved in particular functions, orchestrated with the up-regulation of specific proteins.10a*Cell Transformation10aBiological Models10aGenetic Models10aMessenger/metabolism Signal Transduction Systems Biology10aNeoplastic *Gene Expression Profiling *Gene Expression Regulation10aNeoplastic Humans Male Models10aStatistical Neoplasm Proteins/*physiology Neoplasms/etiology/*genetics Prostatic Neoplasms/genetics Protein Interaction Mapping RNA1 aHernandez, P.1 aHuerta-Cepas, J.1 aMontaner, D.1 aAl-Shahrour, Fatima1 aValls, J.1 aGomez, L.1 aCapella, G.1 aDopazo, J.1 aPujana, M., A.  uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1758491502088nas a2200217   4500008004100000245006100041210006100102300001200163490000800175520132100183653013101504653002201635653001601657100001801673700001601691700001601707700001201723700001601735700001301751856010601764       2007                        eng d00aStructural analyses of a hypothetical minimal metabolism0 aStructural analyses of a hypothetical minimal metabolism  a1751-620 v3623 aBy integrating data from comparative genomics and large-scale deletion studies, we previously proposed a minimal gene set comprising 206 protein-coding genes. To evaluate the consistency of the metabolism encoded by such a minimal genome, we have carried out a series of computational analyses. Firstly, the topology of the minimal metabolism was compared with that of the reconstructed networks from natural bacterial genomes. Secondly, the robustness of the metabolic network was evaluated by simulated mutagenesis and, finally, the stoichiometric consistency was assessed by automatically deriving the steady-state solutions from the reaction set. The results indicated that the proposed minimal metabolism presents stoichiometric consistency and that it is organized as a complex power-law network with topological parameters falling within the expected range for a natural metabolism of its size. The robustness analyses revealed that most random mutations do not alter the topology of the network significantly, but do cause significant damage by preventing the synthesis of several compounds or compromising the stoichiometric consistency of the metabolism. The implications that these results have on the origins of metabolic complexity and the theoretical design of an artificial minimal cell are discussed.10a*Cell Physiological Phenomena Cells/*metabolism Cluster Analysis *Computer Simulation *Metabolic Networks and Pathways *Models10aBiological Models10aStatistical1 aGabaldón, T.1 aPeretó, J.1 aMontero, F.1 aGil, R.1 aLatorre, A.1 aMoya, A.  uhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17510022