The richness and complexity of the molecular regulatory network governing cell proliferation requires a concise and unambiguous method of representation. It is becoming difficult or impossible to keep in mind all of the molecular interactions that may be pertinent to the planning and interpretation of experiments in a given area or to generating functional hypotheses. Difficulties arise especially because of the rich cross-connectivity among different signaling pathways that control cell proliferation and DNA repair. In order to utilize extant information optimally, a road map of the known or suspected molecular interactions would be useful, if not essential. Not only must the information itself be handy, but literature citations for the pertinent evidence must be readily accessible. Moreover, the molecular interaction maps must be in a form that allows frequent updating to accommodate corrections and new data. Molecular interaction maps must be able to cope with the complexities that extensive experimental work has revealed. A diagram convention was therefore devised that allows protein-protein interactions and protein modification states to be clearly represented and that can cope with highly complex systems. During the past year, comprehensive molecular interaction maps were completed of the G1/S cell cycle control network and its connections to DNA repair, replication, and transcription. These maps were published in the August, 1999 issue of Mol. Biol. Cell 10: 2703-2734, together with a presentation of the diagram conventions. Also included were an annotation list for the interactions depicted and reference citations. The map was also placed on our Laboratorys web site where it can be conveniently updated and is publicly accessible (http://discover.nci.nih.gov/kohnk/interaction maps.html). The 109 included mono-molecular species are listed in an alphabetical index which gives the map coordinates where each species can be found. Multimolecular species are depicted by means of a convention of arrowed lines that connect the monomolecular components. Another convention is used to depict the complexities of protein modifications, especially phosphorylations. Symbol conventions also are defined for enzymatic action, stimulation, and inhibition. Each of 194 molecular interactions is marked with a symbol that refers to an annotation list where salient facts and literature references can be found. The maps suggest that many of the components can function as large-scale multiprotein complexes which can assemble at sites of DNA replication, repair, or transcription. The unusual richness of interactions between the p53- MDM2 subsystem and most other subsystems is shown in detail.Work was recently begun on a new molecular interaction map which will extend the representation of cell proliferation control to include signaling from receptors on the cell surface. The symbol conventions were enriched to permit representation of molecular interactions at the plasma membrane, transport between intracellular compartments, and new complexities arising from the interconversions of the various phosphatidylinositol phosphates. Since the global representation of all known growth factor receptors is at this stage prohibitively complicated, the focus will be on signaling from the epidermal growth factor receptors, since we have for these the best molecular interaction data. - Cell Cycle Regulation, Cell Proliferation Control, Molecular Interaction Networks, Molecular interaction Maps, Epidermal Growth Factor Receptor Signaling, DNA Repair,
| Solier, Stephanie; Sordet, Olivier; Kohn, Kurt W et al. (2009) Death receptor-induced activation of the Chk2- and histone H2AX-associated DNA damage response pathways. Mol Cell Biol 29:68-82 |
| Kohn, Kurt W; Aladjem, Mirit I (2006) Circuit diagrams for biological networks. Mol Syst Biol 2:2006.0002 |
| Pommier, Yves; Weinstein, John N; Aladjem, Mirit I et al. (2006) Chk2 molecular interaction map and rationale for Chk2 inhibitors. Clin Cancer Res 12:2657-61 |
| Kohn, Kurt W; Aladjem, Mirit I; Weinstein, John N et al. (2006) Molecular interaction maps of bioregulatory networks: a general rubric for systems biology. Mol Biol Cell 17:1-13 |
| Pommier, Yves; Sordet, Olivier; Rao, V Ashutosh et al. (2005) Targeting chk2 kinase: molecular interaction maps and therapeutic rationale. Curr Pharm Des 11:2855-72 |
| Pommier, Yves; Sordet, Olivier; Antony, Smitha et al. (2004) Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks. Oncogene 23:2934-49 |
| Kohn, Kurt W; Riss, Joseph; Aprelikova, Olga et al. (2004) Properties of switch-like bioregulatory networks studied by simulation of the hypoxia response control system. Mol Biol Cell 15:3042-52 |
| Aladjem, Mirit I; Pasa, Stefania; Parodi, Silvio et al. (2004) Molecular interaction maps--a diagrammatic graphical language for bioregulatory networks. Sci STKE 2004:pe8 |
