Information on molecular interactions operating in biological regulatory networks is rapidly accumulating. The need to integrate this information in the form of functional models is increasingly urgent, but the task is made difficult by the complexity of the interactions being revealed. No consistent convention has developed by which molecular regulatory networks can be diagrammed unambiguously. Moreover, the complexity of the emerging interactions is such that prediction and interpretation of experimental results is becoming increasingly difficult and may require computer simulations. This project aims to develop conventions for 2 kinds of molecular interactions diagrams: (1) heuristic diagrams that can be used to organize information and to trace pathways as on a road map or electric circuit diagram, and (2) well-defined explicit diagrams that can be translated into computer-readable digit strings. Both types of diagrams are designed around the special features of bioregulatory networks: (1) the enzymes are often also substrates for modification, (2) functional species are often multi-protein complexes, and (3) interactions at gene promoters introduce additional complexities. Heuristic diagrams have been prepared of cell cycle regulation in G1 and S phase and of signaling from receptor tyrosine kinase to nuclear genes. The latter shows how a variety of events in different cell compartments can be represented in a comprehensive diagram. A simulation program has been written that can accept as input strings of digits defining the topology of a network as portrayed in an explicit diagram. we are studying the simulated behavior of subsystems of the cell cycle regulatory network. The simulations are being related to experimental data obtained in our Laboratory and elsewhere with the aim of improving our ability to design and interpret experiments. The diagrams and simulation capabilities may help us design potential therapeutic strategies targeted against tumor cells having specific molecular regulatory defects.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Intramural Research (Z01)
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Special Emphasis Panel (LMPH)
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National Cancer Institute Division of Basic Sciences
United States
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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